Assoc. Prof. Michal Otyepka, Ph.D.

Email: michal.otyepka@upol.cz
Adrress:
17. listopadu 12, Olomouc, 771 46, Czech Republic
Phone:
(+420) 58 563 4764
Fax:
(+420) 585 634 761

Tady bude neviditelný text – prázdná mezera

Tady bude neviditelný text – prázdná mezera

Tady bude neviditelný text – prázdná mezera

Professional
2004    Ph.D. Physical chemistry, Palacký University, Olomouc
2007    Doc. (Associate Prof.), Palacký University, Olomouc
2008    Researcher, Institute of Biophysics (group of prof. Šponer), Brno
2009    Head of the Department of Physical Chemistry, Palacký University, Olomouc
2010    Head of the Workpackage „Carbon nanostructures and biomolecules“ of the project RCPTM, Palacký University, Olomouc

Research activities:
Protein (CDK, Cyt. P450) and RNA molecular dynamics, enzyme and ribozyme catalysis, force field development ( chiOL ), QM/MM methods and their applications in biomolecular research. Theoretical study on interations of drugs, antioxidants and Cyt. P450 with membranes. Coauthor of software projects for analysis of molecular channels MOLE and CAVER 1.0. Theoretical design of new 2D materials.

International experience:
2000 (May) at EMBL Heidelberg, Germany, group of prof. R. C. Wade
2005 (Nov.) at SISSA/ISAS Trieste, Italy, group of prof. Paolo Carloni
2006 (Jun.) at SISSA/ISAS Trieste, Italy, group of prof. Paolo Carloni

 

Publication activities:
Author or co-author of more than 50 papers in international journals.
More than 500 citations.
LINK TO RESEARCHER ID

 

 

Selected best publications in last 8 years
1) Ditzler M, Otyepka M, Sponer* J, Walter* N; Molecular Dynamics and Quantum Mechanics of RNA: Conformational and Chemical Change We Can Believe In. Acc. Chem. Res., 43(1), 40-47, 2010
2) Zboril R, Karlický F, Bourlinos* AB, Steriotis TA, Stubos AK, Georgakilas V, Safarova K, Jancik D, Trapalis C, Otyepka* M: Graphene fluoride: a stable stoichiometric graphene derivative and its chemical conversion to graphene. Small, 6 (24), 2010
3) Banas P, Hollas D, Zgarbova M, Jurecka P, Orozco M, Cheatham T, Sponer* J, Otyepka* M: Performance of Molecular Mechanics Force Fields for RNA Simulations. Stability of UUCG and GNRA hairpins. J. Chem. Theor. Comput, 6 (12), 3836-3849, 2010.
4) Florova P, Sklenovsky P, Banas P, Otyepka* M; Explicit water models affect the specific solvation and dynamics of unfolded peptides while the conformational behavior and flexibility of folded peptides remain intact. J. Chem. Theor. Comp., 6(11), 3569-3579, 2010.
5) Sponer JE*, Vázquez-Mayagoitia A, Sumpter BG, Leszczynski J, Sponer J*, Otyepka M, Banas P, Fuentes-Cabrera M*; Theoretical Study on the Intermolecular Interactions of Potentially Primordial Base Pair Analogues. Chemistry Eur. J. 16(10), 3057-3065, 2010
6) Banas P, Walter NG, Sponer* J, Otyepka* M: Protonation States of the Key Active Site Residues and Structural Dynamics of glmS Riboswitch as Revealed by Molecular Dynamics (with Cover Art) J. Phys. Chem. B, 114 (26), 8701-8712, 2010
7) Besseova I, Otyepka M, Reblova K, Sponer* J; Dependence of A-RNA simulations on the choice of the force field and salt strength. Phys. Chem. Chem. Phys., 11, 10701-10711, 2009.
8) Pavlova M, Klvana M, Prokop Z, Chaloupkova R, Banas P, Otyepka M, Wade RC, Tsuda M, Nagata Y, Damborsky* J; Redesigning dehalogenase access tunnels as a strategy for degrading an anthropogenic substrate. Nature Chem. Biol., 5(10), 727-33, 2009
9) Petrek M, Kosinova P, Koca J, Otyepka* M; MOLE: A Voronoi Diagram-based Explorer of Molecular Channels, Pores and Tunnels. Structure 15(11), 1357-1363, 2007
10) Petrek M, Otyepka* M, Banas P, Kosinova P, Koca J, Damborsky* J; CAVER: A new tool to explore routes from protein clefts, pockets and cavities, BMC Bioinformatics 7:316 2006

Show publications

Publications

2011

  • [DOI] V. Mlynsky, P. Banas, N. G. Walter, J. Sponer, and M. Otyepka, “QM/MM Studies of Hairpin Ribozyme Self-Cleavage Suggest the Feasibility
    of Multiple Competing Reaction Mechanisms,” JOURNAL OF PHYSICAL CHEMISTRY B, vol. 115, iss. 47, pp. 13911-13924, 2011.
    [Bibtex]
    @article ISI:000297195400014,
    Author = Mlynsky, Vojtech and Banas, Pavel and Walter, Nils G. and Sponer, Jiri
       and Otyepka, Michal,
    Title = QM/MM Studies of Hairpin Ribozyme Self-Cleavage Suggest the Feasibility
       of Multiple Competing Reaction Mechanisms,
    Journal = JOURNAL OF PHYSICAL CHEMISTRY B,
    Year = 2011,
    Volume = 115,
    Number = 47,
    Pages = 13911-13924,
    Month = DEC 1,
    Abstract = The hairpin ribozyme is a prominent member of small ribozymes since it
       does not require metal ions to achieve catalysis. Guanine 8 (G8) and
       adenine 38 (A38) have been identified as key participants in
       self-cleavage and -ligation. We have carried out hybrid
       quantum-mechanical/molecular mechanical (QM/MM) calculations to evaluate
       the energy along several putative reaction pathways. The error of our
       DFT description of the QM region was tested and shown to be similar to 1
       kcal/mol. We find that self-cleavage of the hairpin ribozyme may follow
       several competing microscopic reaction mechanisms, all with calculated
       activation barriers in good agreement with those from experiment (20-21
       kcal/mol). The initial nucleophilic attack of the A-1(2'-OH) group on
       the scissile phosphate is predicted to be rate-limiting in all these
       mechanisms. An unprotonated G8(-) (together with A38H(+)) yields a
       feasible activation barrier (20.4 kcal/mol). Proton transfer to a
       nonbridging phosphate oxygen also leads to feasible reaction pathways.
       Finally, our calculations consider thio-substitutions of one or both
       nonbridging oxygens of the scissile phosphate and predict that they have
       only a negligible effect on the reaction barrier, as observed
       experimentally.,
    DOI = 10.1021/jp206963g,
    ISSN = 1520-6106,
    Unique-ID = ISI:000297195400014,
    
  • [DOI] J. Granatier, P. Lazar, M. Otyepka, and P. Hobza, “The Nature of the Binding of Au, Ag, and Pd to Benzene, Coronene, and
    Graphene: From Benchmark CCSD(T) Calculations to Plane-Wave DFT
    Calculations,” JOURNAL OF CHEMICAL THEORY AND COMPUTATION, vol. 7, iss. 11, pp. 3743-3755, 2011.
    [Bibtex]
    @article ISI:000296597300030,
    Author = Granatier, Jaroslav and Lazar, Petr and Otyepka, Michal and Hobza, Pavel,
    Title = The Nature of the Binding of Au, Ag, and Pd to Benzene, Coronene, and
       Graphene: From Benchmark CCSD(T) Calculations to Plane-Wave DFT
       Calculations,
    Journal = JOURNAL OF CHEMICAL THEORY AND COMPUTATION,
    Year = 2011,
    Volume = 7,
    Number = 11,
    Pages = 3743-3755,
    Month = NOV,
    Abstract = The adsorption of Ag, Au, and Pd atoms on benzene, coronene, and
       graphene has been studied using post Hartree-Fock wave function theory
       (CCSD(T), MP2) and density functional theory (M06-2X, DFT-D3, PBE,
       vdW-DF) methods. The CCSD(T) benchmark binding energies for benzene-M (M
       = Pd, Au, Ag) complexes are 19.7, 4.2, and 2.3 kcal/mol, respectively.
       We found that the nature of binding of the three metals is different:
       While silver binds predominantly through dispersion interactions, the
       binding of palladium has a covalent character, and the binding of gold
       involves a subtle combination of charge transfer and dispersion
       interactions as well as relativistic effects. We demonstrate that the
       CCSD(T) benchmark binding energies for benzene-M complexes can be
       reproduced in plane-wave density functional theory calculations by
       including a fraction of the exact exchange and a nonempirical van der
       Waals correction (EE+vdW). Applying the EE+vdW method, we obtained
       binding energies for the graphene-M (M = Pd, Au, Ag) complexes of 17.4,
       5.6, and 4.3 kcal/mol, respectively. The trends in binding energies
       found for the benzene M complexes correspond to those in coronene and
       graphene complexes. DFT methods that use empirical corrections to
       account for the effects of vdW interactions significantly overestimate
       binding energies in some of the studied systems.,
    DOI = 10.1021/ct200625h,
    ISSN = 1549-9618,
    Unique-ID = ISI:000296597300030,
    
  • [DOI] K. Berka, T. Hendrychova, P. Anzenbacher, and M. Otyepka, “Membrane Position of Ibuprofen Agrees with Suggested Access Path
    Entrance to Cytochrome P450 2C9 Active Site,” JOURNAL OF PHYSICAL CHEMISTRY A, vol. 115, iss. 41, pp. 11248-11255, 2011.
    [Bibtex]
    @article ISI:000295700600015,
    Author = Berka, Karel and Hendrychova, Tereza and Anzenbacher, Pavel and Otyepka,
       Michal,
    Title = Membrane Position of Ibuprofen Agrees with Suggested Access Path
       Entrance to Cytochrome P450 2C9 Active Site,
    Journal = JOURNAL OF PHYSICAL CHEMISTRY A,
    Year = 2011,
    Volume = 115,
    Number = 41,
    Pages = 11248-11255,
    Month = OCT 20,
    Abstract = Cytochrome P450 2C9 (CYP2C9) is a membrane-anchored human microsomal
       protein involved in the drug metabolism in liver. CYP2C9 consists of an
       N-terminal transmembrane anchor and a catalytic cytoplasmic domain.
       While the structure of the catalytic domain is well-known from X-ray
       experiments, the complete structure and its incorporation into the
       membrane remains unsolved. We constructed an atomistic model of complete
       CYP2C9 in a dioleoylphosphatidylcholine membrane and evolved it by
       molecular dynamics simulations in explicit water on a 100+ ns
       time-scale. The model agrees well with known experimental data about
       membrane positioning of cytochromes P450. The entry to the substrate
       access channel is proposed to be facing the membrane interior while the
       exit of the product egress channel is situated above the interface
       pointing toward the water phase. The positions of openings of the
       substrate access and product egress channels correspond to free energy
       minima of CYP2C9 substrate ibuprofen and its metabolite in the membrane,
       respectively.,
    DOI = 10.1021/jp204488j,
    ISSN = 1089-5639,
    Unique-ID = ISI:000295700600015,
    
  • [DOI] M. Zgarbova, P. Jurecka, P. Banas, M. Otyepka, J. E. Sponer, N. B. Leontis, C. L. Zirbel, and J. Sponer, “Noncanonical Hydrogen Bonding in Nucleic Acids. Benchmark Evaluation of
    Key Base-Phosphate Interactions in Folded RNA Molecules Using
    Quantum-Chemical Calculations and Molecular Dynamics Simulations,” JOURNAL OF PHYSICAL CHEMISTRY A, vol. 115, iss. 41, pp. 11277-11292, 2011.
    [Bibtex]
    @article ISI:000295700600019,
    Author = Zgarbova, Marie and Jurecka, Petr and Banas, Pavel and Otyepka, Michal
       and Sponer, Judit E. and Leontis, Neocles B. and Zirbel, Craig L. and
       Sponer, Jiri,
    Title = Noncanonical Hydrogen Bonding in Nucleic Acids. Benchmark Evaluation of
       Key Base-Phosphate Interactions in Folded RNA Molecules Using
       Quantum-Chemical Calculations and Molecular Dynamics Simulations,
    Journal = JOURNAL OF PHYSICAL CHEMISTRY A,
    Year = 2011,
    Volume = 115,
    Number = 41,
    Pages = 11277-11292,
    Month = OCT 20,
    Abstract = RNA molecules are stabilized by a wide range of non canonical
       interactions that are not present in DNA. Among them, the recently
       classified base phosphate (BPh) interactions belong to the most
       important ones. Twelve percent of nucleotides in the ribosomal crystal
       structures are involved in BPh interactions. BPh interactions are highly
       conserved and provide major constraints on RNA sequence evolution. Here
       we provide assessment of the energetics of BPh interactions using MP2
       computations extrapolated to the complete basis set of atomic orbitals
       and corrected for higher-order electron correlation effects. The
       reference computations are compared with DFT-D and DFT-D3 approaches,
       the SAPT method, and the molecular mechanics force field. The
       computations, besides providing the basic benchmark for the BPh
       interactions, allow some refinements of the original classification,
       including identification of some potential doubly bonded BPh patterns.
       The reference computations are followed by analysis of some larger RNA
       fragments that consider the context of the BPh interactions. The
       computations demonstrate the complexity of interaction patterns
       utilizing the BPh interactions in real RNA structures. The BPh
       interactions are often involved in intricate interaction networks. We
       studied BPh interactions of protonated adenine that can contribute to
       catalysis of hairpin ribozyme, the key BPh interaction in the S-turn
       motif of the sarcin ricin loop, which may predetermine the S-turn
       topology and complex BPh patterns-from the glmS riboswitch. Finally, the
       structural stability of BPh interactions in explicit solvent molecular
       dynamics simulations is assessed. The simulations well preserve key BPh
       interactions and allow dissection of structurally/functionally important
       water-meditated BPh bridges, which could not be considered in earlier
       bioinformatics classification of BPh interactions.,
    DOI = 10.1021/jp204820b,
    ISSN = 1089-5639,
    Unique-ID = ISI:000295700600019,
    
  • [DOI] F. Karlicky and M. Otyepka, “First Step in the Reaction of Zerovalent Iron with Water,” JOURNAL OF CHEMICAL THEORY AND COMPUTATION, vol. 7, iss. 9, pp. 2876-2885, 2011.
    [Bibtex]
    @article ISI:000294790400024,
    Author = Karlicky, Frantisek and Otyepka, Michal,
    Title = First Step in the Reaction of Zerovalent Iron with Water,
    Journal = JOURNAL OF CHEMICAL THEORY AND COMPUTATION,
    Year = 2011,
    Volume = 7,
    Number = 9,
    Pages = 2876-2885,
    Month = SEP,
    Abstract = Here we present a comprehensive quantum chemical study. Of the simplest
       model system for the reactions of nanoscale zerovalent iron, i.e, the
       gas phase reaction of an iron atom with water, to identify a theoretical
       method that provides reasonably accurate geometries and thermochemical
       data for selected iron compounds along the reaction path (Fe, FeO,
       HFeOH, Fe(OH)(2)). The energies of selected stationary points on the
       ground electronic potential energy surface were systematically studied
       using HF and post-HF methods (MP2, MP3, MP4, CCSD, CCSD(T), CASSCF,
       MRCI) and selected DFT functionals (B3LYP, B97-I, BPW91, M06, M06-HF,
       M06-L, M06-2X and MPW1K) using various basis sets up to the complete
       basis set Scalar relativistic effects were modeled using the
       Douglas-Kroll-Hess Hamiltonian to the fourth Order, and the effects of
       valence plus outer core electronic correlation were also evaluated The
       calculations showed that (i) dynamic electron, correlation is crucial
       for accurate modeling of the reactions in question, (ii) the PES around
       the stationary points along the reaction path is rather flat, (iii) the
       single point energies calculated at the CCSD(T)/CBS level are in
       reasonably good agreemeny with experimental measurements, (iv) it is
       difficult to interpret DFT energies in the absence of benchmarking
       against data or results obtained at a level of theory that is known to
       accurately reproduce experimental results, (v) relativistic effects are
       relatively modest in this system but should be included if chemical
       accuracy is desired, and (vi) careful analysis of the multireference
       character of the system and potential spin contamination is important
       The CCSD(T)-3s3p-DKH2/CBS method can be considered the gold standard for
       this reaction because calculations at this level are in good agreement
       with experimental atomic excitation energies and thermochemical data.
       The gas-phase activation energy of the reaction between Fe and H(2)O is
       23.6 kcal/mol including the ZPVE correction (Delta G(298K)(double
       dagger) = 29.2 kcal/mol), and HFeOH is a stable intermediate lying -31.2
       kcal/mol below the reactants (Delta G(298K) = -25.4 kcal/mol).,
    DOI = 10.1021/ct200372y,
    ISSN = 1549-9618,
    Unique-ID = ISI:000294790400024,
    
  • [DOI] M. Zgarbova, M. Otyepka, J. Sponer, A. Mladek, P. Banas, T. E. Cheatham III, and P. Jurecka, “Refinement of the Cornell et al. Nucleic Acids Force Field Based on
    Reference Quantum Chemical Calculations of Glycosidic Torsion Profiles,” JOURNAL OF CHEMICAL THEORY AND COMPUTATION, vol. 7, iss. 9, pp. 2886-2902, 2011.
    [Bibtex]
    @article ISI:000294790400025,
    Author = Zgarbova, Marie and Otyepka, Michal and Sponer, Jiri and Mladek, Arnost
       and Banas, Pavel and Cheatham, III, Thomas E. and Jurecka, Petr,
    Title = Refinement of the Cornell et al. Nucleic Acids Force Field Based on
       Reference Quantum Chemical Calculations of Glycosidic Torsion Profiles,
    Journal = JOURNAL OF CHEMICAL THEORY AND COMPUTATION,
    Year = 2011,
    Volume = 7,
    Number = 9,
    Pages = 2886-2902,
    Month = SEP,
    Abstract = We report a reparameterization of the glycosidic torsion chi of the
       Cornell et al. AMBER force field for RNA, chi(OL) The parameters remove
       destabilization of the anti region found in the ff99 force field and
       thus prevent formation of spurious ladder-like structural distortions in
       RNA simulations. They also improve the description of the syn region and
       the syn anti balance as well as enhance MD simulations of various RNA
       structures. Although chi(OL) can be combined with both ff99 and
       ff99bsc0, we recommend the latter. We do not recommend using chi(OL) for
       B-DNA because it does not improve upon ff99bsc0 for canonical
       structures. However, it might be useful in simulations of DNA molecules
       containing syn nucleotides. Our parametrization is based on high-level
       QM calculations and differs from conventional parametrization approaches
       in that it incorporates some previously neglected solvation-related
       effects (which appear to be essential for obtaining correct
       anti/high-anti balance). Our chi(OL) force field is compared with
       several previous glycosidic torsion parametrizations.,
    DOI = 10.1021/ct200162x,
    ISSN = 1549-9618,
    Unique-ID = ISI:000294790400025,
    
  • [DOI] P. Sklenovsky, P. Florova, P. Banas, K. Reblova, F. Lankas, M. Otyepka, and J. Sponer, “Understanding RNA Flexibility Using Explicit Solvent Simulations: The
    Ribosomal and Group I Intron Reverse Kink-Turn Motifs,” JOURNAL OF CHEMICAL THEORY AND COMPUTATION, vol. 7, iss. 9, pp. 2963-2980, 2011.
    [Bibtex]
    @article ISI:000294790400032,
    Author = Sklenovsky, Petr and Florova, Petra and Banas, Pavel and Reblova, Kamila
       and Lankas, Filip and Otyepka, Michal and Sponer, Jiri,
    Title = Understanding RNA Flexibility Using Explicit Solvent Simulations: The
       Ribosomal and Group I Intron Reverse Kink-Turn Motifs,
    Journal = JOURNAL OF CHEMICAL THEORY AND COMPUTATION,
    Year = 2011,
    Volume = 7,
    Number = 9,
    Pages = 2963-2980,
    Month = SEP,
    Abstract = Reverse kink-turn is a recurrent elbow-like RNA building block occurring
       in the ribosome and in the group I intron. Its sequence signature almost
       matches that of the conventional kink-turn. However, the reverse and
       conventional kink-turns have opposite directions of bending. The reverse
       kink-turn lacks basically any tertiary interaction between its stems. We
       report unrestrained, explicit solvent molecular dynamics simulations of
       ribosomal and intron reverse kink-turns (54 simulations with 7.4 mu s of
       data in total) with different variants (ff94,ff99,ff99bsc0, ff99
       chi(OL), and ff99bsc0 chi(OL)) of the Cornell et al. force field. We
       test several ion conditions and two water models. The simulations
       characterize the directional intrinsic flexibility of reverse kink turns
       pertinent to their folded functional geometries. The reverse kink-turns
       are the most flexible RNA motifs studied so far by explicit solvent
       simulations which are capable at the present simulation time scale to
       spontaneously and reversibly sample a wide range of geometries from
       tightly kinked ones through flexible intermediates up to extended,
       unkinked structures. A possible biochemical role of the flexibility is
       discussed. Among the tested force fields, the latest chi(OL) variant is
       essential to obtaining stable trajectories while all force field
       versions lacking the chi correction are prone to a swift degradation
       toward senseless ladder-like structures of stems, characterized by
       high-anti glycosidic torsions. The type of explicit water model affects
       the simulations considerably more than concentration and the type of
       ions.,
    DOI = 10.1021/ct200204t,
    ISSN = 1549-9618,
    Unique-ID = ISI:000294790400032,
    
  • [DOI] P. Dobes, J. Rezac, J. Fanfrlik, M. Otyepka, and P. Hobza, “Semiempirical Quantum Mechanical Method PM6-DH2X Describes the Geometry
    and Energetics of CK2-Inhibitor Complexes Involving Halogen Bonds Well,
    While the Empirical Potential Fails,” JOURNAL OF PHYSICAL CHEMISTRY B, vol. 115, iss. 26, pp. 8581-8589, 2011.
    [Bibtex]
    @article ISI:000292281200025,
    Author = Dobes, Petr and Rezac, Jan and Fanfrlik, Jindrich and Otyepka, Michal
       and Hobza, Pavel,
    Title = Semiempirical Quantum Mechanical Method PM6-DH2X Describes the Geometry
       and Energetics of CK2-Inhibitor Complexes Involving Halogen Bonds Well,
       While the Empirical Potential Fails,
    Journal = JOURNAL OF PHYSICAL CHEMISTRY B,
    Year = 2011,
    Volume = 115,
    Number = 26,
    Pages = 8581-8589,
    Month = JUL 7,
    Abstract = In the present study, we have investigated complexes of CK2 protein
       kinase with halogenated inhibitors by means of the advanced
       semiempirical quantum mechanical (SQM) PM6 method (called PM6-DH2X),
       which describes various types of noncovalent interactions including
       halogen bonding well. The PM6-DH2X method provides reliable geometries
       of those CK2 protein kinase-inhibitor complexes involving halogen bonds
       that agree well with the X-ray crystal structures. When the Amber
       empirical potential is applied, this agreement becomes considerably
       worse. Similarly, the binding free energies determined by the PM6-DH2X
       SQM method are much closer to the experimental inhibition constants than
       those based on the Amber empirical potential.,
    DOI = 10.1021/jp202149z,
    ISSN = 1520-6106,
    Unique-ID = ISI:000292281200025,
    
  • [DOI] P. Dobes, J. Fanfrlik, J. Rezac, M. Otyepka, and P. Hobza, “Transferable scoring function based on semiempirical quantum mechanical
    PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors,” JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, vol. 25, iss. 3, pp. 223-235, 2011.
    [Bibtex]
    @article ISI:000288179000005,
    Author = Dobes, Petr and Fanfrlik, Jindrich and Rezac, Jan and Otyepka, Michal
       and Hobza, Pavel,
    Title = Transferable scoring function based on semiempirical quantum mechanical
       PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors,
    Journal = JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,
    Year = 2011,
    Volume = 25,
    Number = 3,
    Pages = 223-235,
    Month = MAR,
    Abstract = A semiempirical quantum mechanical PM6-DH2 method accurately covering
       the dispersion interaction and H-bonding was used to score fifteen
       structurally diverse CDK2 inhibitors. The geometries of all the
       complexes were taken from the X-ray structures and were reoptimised by
       the PM6-DH2 method in continuum water. The total scoring function was
       constructed as an estimate of the binding free energy, i.e., as a sum of
       the interaction enthalpy, interaction entropy and the corrections for
       the inhibitor desolvation and deformation energies. The applied scoring
       function contains a clear thermodynamical terms and does not involve any
       adjustable empirical parameter. The best correlations with the
       experimental inhibition constants (ln K (i)) were found for bare
       interaction enthalpy (r (2) = 0.87) and interaction enthalpy corrected
       for ligand desolvation and deformation energies (r (2) = 0.77); when the
       entropic term was considered, however, the correlation becomes worse but
       still acceptable (r (2) = 0.52). The resulting correlation based on the
       PM6-DH2 scoring function is better than previously published function
       based on various docking/scoring, SAR studies or advanced QM/MM
       approach, however, the robustness is limited by number of available
       experimental data used in the correlation. Since a very similar
       correlation between the experimental and theoretical results was found
       also for a different system of the HIV-1 protease, the suggested scoring
       function based on the PM6-DH2 method seems to be applicable in drug
       design, even if diverse protein-ligand complexes have to be ranked.,
    DOI = 10.1007/s10822-011-9413-5,
    ISSN = 0920-654X,
    Unique-ID = ISI:000288179000005,
    
  • K. Berka and M. Otyepka, “Insenstivity to Close Contacts and Inability to Predict Protein
    Foldability,” JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, vol. 28, iss. 4, pp. 633-634, 2011.
    [Bibtex]
    @article ISI:000286482400027,
    Author = Berka, Karel and Otyepka, Michal,
    Title = Insenstivity to Close Contacts and Inability to Predict Protein
       Foldability,
    Journal = JOURNAL OF BIOMOLECULAR STRUCTURE \& DYNAMICS,
    Year = 2011,
    Volume = 28,
    Number = 4,
    Pages = 633-634,
    Month = FEB,
    ISSN = 0739-1102,
    Unique-ID = ISI:000286482400027,
    
  • [DOI] T. Hendrychova, E. Anzenbacherova, J. Hudecek, J. Skopalik, R. Lange, P. Hildebrandt, M. Otyepka, and P. Anzenbacher, “Flexibility of human cytochrome P450 enzymes: Molecular dynamics and
    spectroscopy reveal important function-related variations,” BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, vol. 1814, iss. 1, SI, pp. 58-68, 2011.
    [Bibtex]
    @article ISI:000285277900009,
    Author = Hendrychova, Tereza and Anzenbacherova, Eva and Hudecek, Jiri and
       Skopalik, Josef and Lange, Reinhard and Hildebrandt, Peter and Otyepka,
       Michal and Anzenbacher, Pavel,
    Title = Flexibility of human cytochrome P450 enzymes: Molecular dynamics and
       spectroscopy reveal important function-related variations,
    Journal = BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS,
    Year = 2011,
    Volume = 1814,
    Number = 1, SI,
    Pages = 58-68,
    Month = JAN,
    Abstract = To gain more complete insight into flexibility and malleability of five
       forms of human liver cytochrome P450 enzymes, which play major roles in
       drug metabolism (CYPs 1A2, 2A6, 2C9, 2D6 and 3A4), we employed UV/VIS
       and resonance Raman spectroscopy in combination with all-atomic
       molecular dynamics simulations under normal and high pressure conditions
       (300 MPa). In general, the high pressure reduces the flexibility of
       CYPs, which become more dense and compact as their radii of gyration and
       temperature B-factors diminish. The flexibility of CYPs spans the
       regions, which are localized in solvent exposed loops. A considerable
       degree of flexibility is also observed at amino-acids making the pw2 and
       solvent channels, which are suggested to serve for substrate access
       and/or product release. The number of water molecules as well as the
       number of protein backbone atoms of the active site in close proximity
       of heme cofactor generally increases under high pressure. This finding
       provides new insights regarding the interpretation of pressure-related
       Soret band red shifts. Presented results also point towards considerable
       differences between the CYP forms studied: CYP2A6 and CYP1A2 have the
       least malleable active sites while those of CYP2D6, CYP2C9 and CYP3A4
       have considerably greater degrees of flexibility or malleability. In
       addition, the number of water molecules in the active site cavity of
       CYP3A4 anomalously decreases under high pressure due to opening of the
       active site. These results correlate with the known substrate
       promiscuity of the respective CYP forms, with CYP3A4 displaying the
       highest substrate promiscuity, corresponding to the most open and
       malleable active site, whereas CYP1A2 and CYP2A6 show a high
       substrate-specificity and have a small and rigid active sites. (C) 2010
       Elsevier B.V. All rights reserved.,
    DOI = 10.1016/j.bbapap.2010.07.017,
    ISSN = 1570-9639,
    Unique-ID = ISI:000285277900009,
    

2010

  • [DOI] R. Zboril, F. Karlicky, A. B. Bourlinos, T. A. Steriotis, A. K. Stubos, V. Georgakilas, K. Safarova, D. Jancik, C. Trapalis, and M. Otyepka, “Graphene Fluoride: A Stable Stoichiometric Graphene Derivative and its
    Chemical Conversion to Graphene,” SMALL, vol. 6, iss. 24, pp. 2885-2891, 2010.
    [Bibtex]
    @article ISI:000285793900015,
    Author = Zboril, Radek and Karlicky, Frantisek and Bourlinos, Athanasios B. and
       Steriotis, Theodore A. and Stubos, Athanasios K. and Georgakilas,
       Vasilios and Safarova, Klara and Jancik, Dalibor and Trapalis, Christos
       and Otyepka, Michal,
    Title = Graphene Fluoride: A Stable Stoichiometric Graphene Derivative and its
       Chemical Conversion to Graphene,
    Journal = SMALL,
    Year = 2010,
    Volume = 6,
    Number = 24,
    Pages = 2885-2891,
    Month = DEC 20,
    Abstract = Stoichoimetric graphene fluoride monolayers are obtained in a single
       step by the liquid-phase exfoliation of graphite fluoride with
       sulfolane. Comparative quantum-mechanical calculations reveal that
       graphene fluoride is the most thermodynamically stable of five studied
       hypothetical graphene derivatives; graphane, graphene fluoride, bromide,
       chloride, and iodide. The graphene fluoride is transformed into graphene
       via graphene iodide, a spontaneously decomposing intermediate. The
       calculated bandgaps of graphene halides vary from zero for graphene
       bromide to 3.1 eV for graphene fluoride. It is possible to design the
       electronic properties of such two-dimensional crystals.,
    DOI = 10.1002/smll.201001401,
    ISSN = 1613-6810,
    Unique-ID = ISI:000285793900015,
    
  • [DOI] A. Mladek, J. E. Sponer, P. Jurecka, P. Banas, M. Otyepka, D. Svozil, and J. Sponer, “Conformational Energies of DNA Sugar-Phosphate Backbone: Reference QM
    Calculations and a Comparison with Density Functional Theory and
    Molecular Mechanics,” JOURNAL OF CHEMICAL THEORY AND COMPUTATION, vol. 6, iss. 12, pp. 3817-3835, 2010.
    [Bibtex]
    @article ISI:000285217000018,
    Author = Mladek, Arnost and Sponer, Judit E. and Jurecka, Petr and Banas, Pavel
       and Otyepka, Michal and Svozil, Daniel and Sponer, Jiri,
    Title = Conformational Energies of DNA Sugar-Phosphate Backbone: Reference QM
       Calculations and a Comparison with Density Functional Theory and
       Molecular Mechanics,
    Journal = JOURNAL OF CHEMICAL THEORY AND COMPUTATION,
    Year = 2010,
    Volume = 6,
    Number = 12,
    Pages = 3817-3835,
    Month = DEC,
    Abstract = The study investigates electronic structure and gas-phase energetics of
       the DNA sugar phosphate backbone via advanced quantum chemical (QM)
       methods. The analysis has been carried out on biologically relevant
       backbone conformations composed of 11 canonical BI-DNA structures, 8
       pathological structures with alpha/gamma torsion angles in the g+/t
       region, and 3 real noncanonical gamma-trans structures occurring in the
       loop region of guanine quadruplex DNA. The influence of backbone
       conformation on the intrinsic energetics was primarily studied using a
       model system consisting of two sugar moieties linked together via a
       phosphodiester bond (SPSOM model). To get the conformation of the
       studied system fully under control, for each calculation we have frozen
       majority of the dihedral angles to their target values. CCSD(T) energies
       extrapolated to the complete basis set were utilized as reference
       values. However, the calculations show that inclusion of higher-order
       electron correlation effects for this system is not crucial and complete
       basis set second-order perturbation calculations are sufficiently
       accurate. The reference QM data are used to assess performance of 10
       contemporary density functionals with the best performance delivered by
       the PBE-D/TZVPP combination along with the Grimme's dispersion
       correction, and by the TPSS-D/6-311++G(3df,3pd) augmented by Jurecka's
       dispersion term. In addition, the QM calculations are compared to
       molecular mechanics (MM) model based on the Cornell et al. force field.
       The destabilization of the pathological g+/t conformers with respect to
       the reference canonical structure and the network of intramolecular CH
       center dot center dot center dot O interactions were investigated by
       means of natural bond orbital analysis (NBO) and atoms-in-molecules
       (AIM) Bader analysis. Finally, four additional model systems of
       different sizes were assessed by comparing their energetics to that of
       the SPSOM system. Energetics of smaller MOSPM model consisting of a
       sugar moiety linked to a phosphate group and capped with methyl and
       methoxy group on the 5'- and 3'-ends, respectively, is fairly similar to
       that of SPSOM, while the role of undesired intramolecular interactions
       is diminished.,
    DOI = 10.1021/ct1004593,
    ISSN = 1549-9618,
    Unique-ID = ISI:000285217000018,
    
  • [DOI] P. Banas, D. Hollas, M. Zgarbova, P. Jurecka, M. Orozco, T. E. Cheatham III, J. Sponer, and M. Otyepka, “Performance of Molecular Mechanics Force Fields for RNA Simulations:
    Stability of UUCG and GNRA Hairpins,” JOURNAL OF CHEMICAL THEORY AND COMPUTATION, vol. 6, iss. 12, pp. 3836-3849, 2010.
    [Bibtex]
    @article ISI:000285217000019,
    Author = Banas, Pavel and Hollas, Daniel and Zgarbova, Marie and Jurecka, Petr
       and Orozco, Modesto and Cheatham, III, Thomas E. and Sponer, Jiri and
       Otyepka, Michal,
    Title = Performance of Molecular Mechanics Force Fields for RNA Simulations:
       Stability of UUCG and GNRA Hairpins,
    Journal = JOURNAL OF CHEMICAL THEORY AND COMPUTATION,
    Year = 2010,
    Volume = 6,
    Number = 12,
    Pages = 3836-3849,
    Month = DEC,
    Abstract = The RNA hairpin loops represent important RNA topologies with
       indispensable biological functions in RNA folding and tertiary
       interactions. 5'-UNCG-3' and 5'-GNRA-3' RNA tetraloops are the most
       important classes of RNA hairpin loops. Both tetraloops are highly
       structured with characteristic signature three-dimensional features and
       are recurrently seen in functional RNAs and ribonucleoprotein particles.
       Explicit solvent molecular dynamics (MD) simulation is a computational
       technique which can efficiently complement the experimental data and
       provide unique structural dynamics information on the atomic scale.
       Nevertheless, the outcome of simulations is often compromised by
       imperfections in the parametrization of simplified pairwise additive
       empirical potentials referred to also as force fields. We have pointed
       out in several recent studies that a force field description of
       single-stranded hairpin segments of nucleic acids may be particularly
       challenging for the force fields. In this paper, we report a critical
       assessment of a broad set of MD simulations of UUCG, GAGA, and GAAA
       tetraloops using various force fields. First, we utilized the three
       widely used variants of Cornell et al. (AMBER) force fields known as
       694, 699, and ff99bsc0. Some simulations were also carried out with
       CHARMM27. The simulations reveal several problems which show that these
       force fields are not able to retain all characteristic structural
       features (structural signature) of the studied tetraloops. Then we
       tested four recent reparameterizations of glycosidic torsion of the
       Cornell et al. force field (two of them being currently parametrized in
       our laboratories). We show that at least some of the new versions show
       an improved description of the tetraloops, mainly in the syn glycosidic
       torsion region of the UNCG tetraloop. The best performance is achieved
       in combination with the bsc0 parametrization of the alpha/gamma angles.
       Another critically important region to properly describe RNA molecules
       is the anti/high-anti region of the glycosidic torsion, where there are
       significant differences among the tested force fields. The tetraloop
       simulations are complemented by simulations of short A-RNA stems, which
       are especially sensitive to an appropriate description of the
       anti/high-anti region. While excessive accessibility of the high-anti
       region converts the A-RNA into a senseless ``ladder-like'' geometry,
       excessive penalization of the high-anti region shifts the simulated
       structures away from typical A-RNA geometry to structures with a visibly
       underestimated inclination of base pairs with respect to the helical
       axis.,
    DOI = 10.1021/ct100481h,
    ISSN = 1549-9618,
    Unique-ID = ISI:000285217000019,
    
  • [DOI] P. Florova, P. Sklenovsky, P. Banas, and M. Otyepka, “Explicit Water Models Affect the Specific Solvation and Dynamics of
    Unfolded Peptides While the Conformational Behavior and Flexibility of
    Folded Peptides Remain Intact,” JOURNAL OF CHEMICAL THEORY AND COMPUTATION, vol. 6, iss. 11, 3285, pp. 3569-3579, 2010.
    [Bibtex]
    @article ISI:000283884300026,
    Author = Florova, Petra and Sklenovsky, Petr and Banas, Pavel and Otyepka, Michal,
    Title = Explicit Water Models Affect the Specific Solvation and Dynamics of
       Unfolded Peptides While the Conformational Behavior and Flexibility of
       Folded Peptides Remain Intact,
    Journal = JOURNAL OF CHEMICAL THEORY AND COMPUTATION,
    Year = 2010,
    Volume = 6,
    Number = 11, 3285,
    Pages = 3569-3579,
    Month = NOV,
    Abstract = Conventional molecular dynamics simulations on 50 ns to 1 mu s time
       scales were used to study the effects of explicit solvent models on the
       conformational behavior and solvation of two oligopeptide solutes:
       alpha-helical EK-peptide (14 amino acids) and a beta-hairpin chignolin
       (10 amino acids). The widely used AMBER force fields (ff99, ff99SB, and
       ff03) were combined with four of the most commonly used explicit solvent
       models (TIP3P, TIP4P, TIP5P, and SPC/E). Significant differences in the
       specific solvation of chignolin among the studied water models were
       identified. Chignolin was highly solvated in TIP5P, whereas reduced
       specific solvation was found in the TIP4P, SPC/E, and TIP3P models for
       kinetic, thermodynamic, and both kinetic and thermodynamic reasons,
       respectively. The differences in specific solvation did not influence
       the dynamics of structured parts of the folded peptide. However,
       substantial differences between TIP5P and the other models were observed
       in the dynamics of unfolded chignolin, stability of salt bridges, and
       specific solvation of the backbone carbonyls of EK-peptide. Thus, we
       conclude that the choice of water model may affect the dynamics of
       flexible parts of proteins that are solvent-exposed. On the other hand,
       all water models should perform similarly for well-structured folded
       protein regions. The merits of the TIP3P model include its high and
       overestimated mobility, which accelerates simulation processes and thus
       effectively increases sampling.,
    DOI = 10.1021/ct1003687,
    ISSN = 1549-9618,
    Unique-ID = ISI:000283884300026,
    
  • [DOI] P. Banas, N. G. Walter, J. Sponer, and M. Otyepka, “Protonation States of the Key Active Site Residues and Structural
    Dynamics of the glmS Riboswitch As Revealed by Molecular Dynamics,” JOURNAL OF PHYSICAL CHEMISTRY B, vol. 114, iss. 26, pp. 8701-8712, 2010.
    [Bibtex]
    @article ISI:000279282600015,
    Author = Banas, Pavel and Walter, Nils G. and Sponer, Jiri and Otyepka, Michal,
    Title = Protonation States of the Key Active Site Residues and Structural
       Dynamics of the glmS Riboswitch As Revealed by Molecular Dynamics,
    Journal = JOURNAL OF PHYSICAL CHEMISTRY B,
    Year = 2010,
    Volume = 114,
    Number = 26,
    Pages = 8701-8712,
    Month = JUL 8,
    Abstract = The glmS catalytic riboswitch is part of the 5'-untranslated region of
       mRNAs encoding glucosamine-6-phosphate (GlcN6P) synthetase (glmS) in
       numerous Gram-positive bacteria. Binding of the cofactor GlcN6P induces
       site-specific self-cleavage of the RNA. However, the detailed reaction
       mechanism as well as the protonation state of the glmS reactive form
       still remains elusive. To probe the dominant protonation states of key
       active site residues, we carried out explicit solvent molecular dynamic
       simulations involving various protonation states of three crucial active
       site moieties observed in the available crystal structures: (i) guanine
       G40 (following the Thermoanaerobacter tengcongensis numbering), (ii) the
       GlcN6P amino/ammonium group, and (iii) the GlcN6P phosphate moiety. We
       found that a deprotonated G40(-) seems incompatible with the observed
       glmS active site architecture. Our data suggest that the canonical form
       of G40 plays a structural role by stabilizing an in-line attack
       conformation of the cleavage site A-1(2'-OH) nucleophile, rather than a
       more direct chemical role. In addition, we observe weakened cofactor
       binding upon protonation of the GlcN6P phosphate moiety, which explains
       the experimentally observed increase in K(m) with decreasing pH.
       Finally, we discuss a possible role of cofactor binding and its
       interaction with the G65 and Gl purines in structural stabilization of
       the A-1(2'-01-I) in-line attack conformation. On the basis of the
       identified dominant protonation state of the reaction precursor, we
       propose a hypothesis of the self-cleavage mechanism in which A-1(2'-OH)
       is activated as a nucleophile by the Gl (pro-R(p)) nonbridging oxygen of
       the scissile phosphate, whereas the ammonium group of GlcN6P acts as the
       general acid protonating the Gl(O5') leaving group.,
    DOI = 10.1021/jp9109699,
    ISSN = 1520-6106,
    Unique-ID = ISI:000279282600015,
    
  • [DOI] E. S. Child, T. Hendrychova, K. McCague, A. Futreal, M. Otyepka, and D. J. Mann, “A cancer-derived mutation in the PSTAIRE helix of cyclin-dependent
    kinase 2 alters the stability of cyclin binding,” BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, vol. 1803, iss. 7, pp. 858-864, 2010.
    [Bibtex]
    @article ISI:000279093300010,
    Author = Child, Emma S. and Hendrychova, Tereza and McCague, Karen and Futreal,
       Andy and Otyepka, Michal and Mann, David J.,
    Title = A cancer-derived mutation in the PSTAIRE helix of cyclin-dependent
       kinase 2 alters the stability of cyclin binding,
    Journal = BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH,
    Year = 2010,
    Volume = 1803,
    Number = 7,
    Pages = 858-864,
    Month = JUL,
    Abstract = Cyclin-dependent kinase 2 (cdk2) is a central regulator of the mammalian
       cell cycle. Here we describe the properties of a mutant form of cdk2
       identified during large-scale sequencing of protein kinases from
       cancerous tissue. The mutation substituted a leucine for a proline in
       the PSTAIRE helix, the central motif in the interaction of the cdk with
       its regulatory cyclin subunit. We demonstrate that whilst the mutant
       cdk2 is considerably impaired in stable cyclin association, it is still
       able to generate an active kinase that can functionally complement
       defective cdks in vivo. Molecular dynamic simulations and biophysical
       measurements indicate that the observed biochemical properties likely
       stem from increased flexibility within the cyclin-binding helix. (C)
       2010 Elsevier By. All rights reserved.,
    DOI = 10.1016/j.bbamcr.2010.04.004,
    ISSN = 0167-4889,
    Unique-ID = ISI:000279093300010,
    
  • [DOI] V. Mlynsky, P. Banas, D. Hollas, K. Reblova, N. G. Walter, J. Sponer, and M. Otyepka, “Extensive Molecular Dynamics Simulations Showing That Canonical G8 and
    Protonated A38H(+) Forms Are Most Consistent with Crystal Structures of
    Hairpin Ribozyme,” JOURNAL OF PHYSICAL CHEMISTRY B, vol. 114, iss. 19, pp. 6642-6652, 2010.
    [Bibtex]
    @article ISI:000277499700047,
    Author = Mlynsky, Vojtech and Banas, Pavel and Hollas, Daniel and Reblova, Kamila
       and Walter, Nils G. and Sponer, Jiri and Otyepka, Michal,
    Title = Extensive Molecular Dynamics Simulations Showing That Canonical G8 and
       Protonated A38H(+) Forms Are Most Consistent with Crystal Structures of
       Hairpin Ribozyme,
    Journal = JOURNAL OF PHYSICAL CHEMISTRY B,
    Year = 2010,
    Volume = 114,
    Number = 19,
    Pages = 6642-6652,
    Month = MAY 20,
    Abstract = The hairpin ribozyme is a prominent member of the group of small
       catalytic RNAs (RNA enzymes or ribozymes) because it does not require
       metal ions to achieve catalysis. Biochemical and structural data have
       implicated guanine 8 (G8) and adenine 38 (A38) as catalytic participants
       in cleavage and ligation catalyzed by the hairpin ribozyme, yet their
       exact role in catalysis remains disputed. To gain insight into dynamics
       in the active site of a minimal self-cleaving hairpin ribozyme, we have
       performed extensive classical, explicit-solvent molecular dynamics (MD)
       simulations on time scales of 50-150 ns. Starting from the available
       X-ray crystal structures, we investigated the structural impact of the
       protonation states of G8 and A38, and the inactivating A-1(2'-methoxy)
       substitution employed in crystallography. Our simulations reveal that a
       canonical G8 agrees well with the crystal structures while a
       deprotonated G8 profoundly distorts the active site. Thus MD simulations
       do not support a straightforward participation of the deprotonated G8 in
       catalysis. By comparison, the G8 enol tautomer is structurally well
       tolerated, causing only local rearrangements in the active site.
       Furthermore, a protonated A38H(+) is more consistent with the
       crystallography data than a canonical A38. The simulations thus support
       the notion that A38H+ is the dominant form in the crystals, grown at pH
       6. In most simulations, the canonical A38 departs from the scissile
       phosphate and substantially perturbs the structures of the active site
       and S-turn. Yet, we occasionally also observe formation of a stable
       A-1(2'-OH)center dot center dot center dot A38(N1) hydrogen bond, which
       documents the ability of the ribozyme to form this hydrogen bond,
       consistent with a potential role of A38 as general base catalyst. The
       presence of this hydrogen bond is, however, incompatible with the
       expected in-line attack angle necessary for self-cleavage, requiring a
       rapid transition of the deprotonated 2'-oxyanion to a position more
       favorable for in-line attack after proton transfer from A-1(2'-OH) to
       A38(N1). The simulations revealed a potential force field artifact,
       occasional but irreversible formation of ``ladder-like'', underwound
       A-RNA structure in one of the external helices. Although it does not
       affect the catalytic center of the hairpin ribozyme, further studies are
       under way to better assess possible influence of such force field
       behavior on long RNA simulations.,
    DOI = 10.1021/jp1001258,
    ISSN = 1520-6106,
    Unique-ID = ISI:000277499700047,
    
  • [DOI] K. Dvorakova-Hola, A. Matuskova, M. Kubala, M. Otyepka, T. Kucera, J. Vecer, P. Herman, N. Parkhomenko, E. Kutejova, and J. Janata, “Glycine-Rich Loop of Mitochondrial Processing Peptidase alpha-Subunit Is
    Responsible for Substrate Recognition by a Mechanism Analogous to
    Mitochondrial Receptor Tom20,” JOURNAL OF MOLECULAR BIOLOGY, vol. 396, iss. 5, pp. 1197-1210, 2010.
    [Bibtex]
    @article ISI:000275691500002,
    Author = Dvorakova-Hola, Klara and Matuskova, Anna and Kubala, Martin and
       Otyepka, Michal and Kucera, Tomas and Vecer, Jaroslav and Herman, Petr
       and Parkhomenko, Natalya and Kutejova, Eva and Janata, Jiri,
    Title = Glycine-Rich Loop of Mitochondrial Processing Peptidase alpha-Subunit Is
       Responsible for Substrate Recognition by a Mechanism Analogous to
       Mitochondrial Receptor Tom20,
    Journal = JOURNAL OF MOLECULAR BIOLOGY,
    Year = 2010,
    Volume = 396,
    Number = 5,
    Pages = 1197-1210,
    Month = MAR 12,
    Abstract = Tryptophan fluorescence measurements were used to characterize the local
       dynamics of the highly conserved glycine-rich loop (GRL) of the
       mitochondrial processing peptidase (MPP) alpha-subunit in the presence
       of the substrate precursor. Reporter tryptophan residue was introduced
       into the GRL of the yeast alpha-MPP (Y299W) or at a proximal site
       (Y303W). Time-resolved and steady-state fluorescence spectroscopy
       demonstrated that for Trp299, the primary contact with the yeast malate
       dehydrogenase precursor evokes a change of the local GRL mobility.
       Moreover, time-resolved measurements showed that a functionless
       alpha-MPP with a single-residue deletion in the loop (Y303W/Delta G292)
       is defective particularly in the primary contact with substrate. Thus,
       the GRL was proved to be part of a contact site of the enzyme
       specifically recognizing the substrate. Regarding the surface exposure
       and presence of the hydrophobic patches within the GRL, we proposed a
       functional analogy between the presequence recognition by the
       hydrophobic binding groove of the Tom20 mitochondrial import receptor
       and the GRL of the alpha-MPP. A molecular dynamics (MD) simulation of
       the MPP-substrate peptide complex model was employed to test this
       hypothesis. The initial positioning and conformation of the substrate
       peptide in the model fitting were chosen based on the analogy of its
       interaction with the Tom20 binding groove. MD simulation confirmed the
       stability of the proposed interaction and showed also a decrease in GRL
       flexibility in the presence of substrate, in agreement with fluorescence
       measurements. Moreover, conserved substrate hydrophobic residues in
       positions +1 and -4 to the cleavage site remain in close contact with
       the side chains of the GRL during the entire production part of MD
       simulation as stabilizing points of the hydrophobic interaction. We
       conclude that the GRL of the MPP alpha-subunit is the crucial
       evolutional outcome of the presequence recognition by MPP and represents
       a functional parallel with Tom20 import receptor. (C) 2010 Elsevier Ltd.
       All rights reserved.,
    DOI = 10.1016/j.jmb.2009.12.054,
    ISSN = 0022-2836,
    Unique-ID = ISI:000275691500002,
    
  • P. Sklenovsky and M. Otyepka, “In Silico Structural and Functional Analysis of Fragments of the Ankyrin
    Repeat Protein P18(INK4c),” JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, vol. 27, iss. 4, pp. 521-539, 2010.
    [Bibtex]
    @article ISI:000272599400011,
    Author = Sklenovsky, Petr and Otyepka, Michal,
    Title = In Silico Structural and Functional Analysis of Fragments of the Ankyrin
       Repeat Protein P18(INK4c),
    Journal = JOURNAL OF BIOMOLECULAR STRUCTURE \& DYNAMICS,
    Year = 2010,
    Volume = 27,
    Number = 4,
    Pages = 521-539,
    Month = FEB,
    Abstract = Ankyrin repeat proteins (ARPs) are ubiquitous proteins that play
       critical regulatory roles in organisms and consist of repeating motifs
       (ankyrin repeats) stacked in non-globular, almost linear, ``quasi
       one-dimensional'' configurations. They also have highly unusual
       mechanical properties, notably ARPs can behave as nano-springs. Both
       their essential cellular functions and distinctive nano-mechanical
       properties have aroused interest in ARPs for potential applications in
       medicine and nanotechnology. Further, the modular architecture of ARPs,
       which lack the long-range contacts that typically stabilize globular
       proteins, provides a new paradigm for understanding protein stability
       and folding mechanisms of proteins. In the present study, the stability
       of ARP p18(INK4c) (p18) and fifty p18 fragments was investigated by
       all-atomic molecular dynamics (MD) simulations in explicit water on a
       similar to 3.3 microseconds timescale. The fragment simulations indicate
       that p18 alpha-helices are significantly stabilized by tertiary
       interactions, because in the absence of their native context they
       readily melt. All single p18 ARs and their structural elements are also
       unstable outside their native context. The minimal stable motifs are
       pairs of ARs, implying that inter-repeat contacts are essential for AR
       stability. Further, pairs of internal ARs are less stable than pairs
       that include a native capping AR. The MD simulations also provide
       indications of the functional roles of p18 turns and loops: the turns
       appear to be essential for the stability of the protein, while the loops
       both help to stabilize the p18 structure and are involved in recognition
       processes. Temperature-induced unfolding analysis shows that the p18
       melts from the N-terminus to the C-terminus.,
    ISSN = 0739-1102,
    Unique-ID = ISI:000272599400011,
    
  • [DOI] M. A. Ditzler, M. Otyepka, J. Sponer, and N. G. Walter, “Molecular Dynamics and Quantum Mechanics of RNA: Conformational and
    Chemical Change We Can Believe In,” ACCOUNTS OF CHEMICAL RESEARCH, vol. 43, iss. 1, pp. 40-47, 2010.
    [Bibtex]
    @article ISI:000274289400005,
    Author = Ditzler, Mark A. and Otyepka, Michal and Sponer, Jiri and Walter, Nils
       G.,
    Title = Molecular Dynamics and Quantum Mechanics of RNA: Conformational and
       Chemical Change We Can Believe In,
    Journal = ACCOUNTS OF CHEMICAL RESEARCH,
    Year = 2010,
    Volume = 43,
    Number = 1,
    Pages = 40-47,
    Month = JAN,
    Abstract = Structure and dynamics are both critical to RNA's vital functions in
       biology. Numerous techniques can elucidate the structural dynamics of
       RNA, but computational approaches based on experimental data arguably
       hold the promise of providing the most detail. In this Account, we
       highlight areas wherein molecular dynamics (MD) and quantum mechanical
       (QM) techniques are applied to RNA, particularly in relation to
       complementary experimental studies.
       We have expanded on atomic-resolution crystal structures of RNAs in
       functionally relevant states by applying explicit Solvent MD simulations
       to explore their dynamics and conformational changes on the
       submicrosecond time scale. MD relies simplified atomistic, pairwise
       additive interaction potentials (force fields). Because of limited
       sampling, due to the finite accessible simulation time scale and the
       approximated force field, high-quality starting structures are required.
       Despite their imperfection, we find that currently available force
       fields empower MD to provide meaningful and predictive information on
       RNA dynamics around a crystallographically defined energy minimum. The
       performance of force fields can be estimated by precise QM calculations
       on small model systems. Such calculations agree reasonably well with the
       Cornell et al. AMBER force field, particularly for stacking and
       hydrogen-bonding interactions. A final verification of any force field
       is accomplished by simulations of complex nucleic acid structures.
       The performance of the Cornell et al. AMBER force field generally
       corresponds well with and augments experimental data, but one notable
       exception could be the capping loops of double-helical stems. In
       addition, the performance of pairwise additive force fields is obviously
       unsatisfactory for inclusion of divalent cations, because their
       interactions lead to major polarization and charge-transfer effects
       neglected by the force field. Neglect of polarization also limits,
       albeit to a lesser extent, the description accuracy of other
       contributions, such as interactions with monovalent ions, conformational
       flexibility of the anionic sugar-phosphate backbone, hydrogen bonding,
       and solute polarization by solvent. Still, despite limitations, MD
       simulations are a valid tool for analyzing the structural dynamics of
       existing experimental structures. Careful analysis of MD simulations can
       identify problematic aspects of an experimental RNA structure, unveil
       structural characteristics masked by experimental constraints, reveal
       functionally significant stochastic fluctuations, evaluate the
       structural role of base ionization, and predict structurally and
       potentially functionally important details of the solvent behavior,
       including the presence of tightly bound water molecules. Moreover,
       combining classical MD simulations with QM calculations in hybrid QM/MM
       approaches helps in the assessment of the plausibility of chemical
       mechanisms of catalytic RNAs (ribozymes).
       In contrast, the reliable prediction of structure from sequence
       information is beyond the applicability of MD tools. The ultimate
       utility of computational studies in understanding RNA function thus
       requires that the results are neither blindly accepted nor flatly
       rejected, but rather considered in the context of all available
       experimental data, with great care given to assessing limitations
       through the available starting structures, force field approximations,
       and sampling limitations. The examples given in this Account showcase
       how the judicious use of basic MD simulations has already served as a
       powerful tool to help evaluate the role of structural dynamics in
       biological function of RNA.,
    DOI = 10.1021/ar900093g,
    ISSN = 0001-4842,
    Unique-ID = ISI:000274289400005,
    
  • [DOI] J. E. Sponer, A. Vazquez-Mayagoitia, B. G. Sumpter, J. Leszczynski, J. Sponer, M. Otyepka, P. Banas, and M. Fuentes-Cabrera, “Theoretical Studies on the Intermolecular Interactions of Potentially
    Primordial Base-Pair Analogues,” CHEMISTRY-A EUROPEAN JOURNAL, vol. 16, iss. 10, pp. 3057-3065, 2010.
    [Bibtex]
    @article ISI:000275943400013,
    Author = Sponer, Judit E. and Vazquez-Mayagoitia, Alvaro and Sumpter, Bobby G.
       and Leszczynski, Jerzy and Sponer, Jiri and Otyepka, Michal and Banas,
       Pavel and Fuentes-Cabrera, Miguel,
    Title = Theoretical Studies on the Intermolecular Interactions of Potentially
       Primordial Base-Pair Analogues,
    Journal = CHEMISTRY-A EUROPEAN JOURNAL,
    Year = 2010,
    Volume = 16,
    Number = 10,
    Pages = 3057-3065,
    Abstract = Recent experimental studies on the Watson-Crick type base pairing of
       triazine and aminopyrimidine derivatives suggest that acid/base
       properties of the constituent bases might be related to the duplex
       stabilities measured in solution. Herein we use high-level quantum
       chemical calculations and molecular dynamics simulations to evaluate the
       base pairing and stacking interactions of seven selected base pairs,
       which are common in that they are stabilized by two N-H center dot
       center dot center dot O hydrogen bonds separated by one N-H center dot
       center dot center dot N hydrogen bond. We show that neither the base
       pairing nor the base stacking interaction energies correlate with the
       reported pK(a) data of the bases and the melting points of the duplexes.
       This suggests that the experimentally observed correlation between the
       melting point data of the duplexes and the pKa values of the constituent
       bases is not rooted in the intrinsic base pairing and stacking
       properties. The physical chemistry origin of the observed experimental
       correlation thus remains unexplained and requires further
       investigations. In addition, since out-calculations are carried out with
       extrapolation to the complete basis set of atomic orbitals and with
       inclusion of higher electron correlation effects, they provide reference
       data for stacking and base pairing energies of non-natural bases.,
    DOI = 10.1002/chem.200902068,
    ISSN = 0947-6539,
    Unique-ID = ISI:000275943400013,
    
  • [DOI] M. Zgarbova, M. Otyepka, J. Sponer, P. Hobza, and P. Jurecka, “Large-scale compensation of errors in pairwise-additive empirical force
    fields: comparison of AMBER intermolecular terms with rigorous DFT-SAPT
    calculations,” PHYSICAL CHEMISTRY CHEMICAL PHYSICS, vol. 12, iss. 35, pp. 10476-10493, 2010.
    [Bibtex]
    @article ISI:000281352300043,
    Author = Zgarbova, Marie and Otyepka, Michal and Sponer, Jiri and Hobza, Pavel
       and Jurecka, Petr,
    Title = Large-scale compensation of errors in pairwise-additive empirical force
       fields: comparison of AMBER intermolecular terms with rigorous DFT-SAPT
       calculations,
    Journal = PHYSICAL CHEMISTRY CHEMICAL PHYSICS,
    Year = 2010,
    Volume = 12,
    Number = 35,
    Pages = 10476-10493,
    Abstract = The intermolecular interaction energy components for several molecular
       complexes were calculated using force fields available in the AMBER
       suite of programs and compared with Density Functional Theory-Symmetry
       Adapted Perturbation Theory (DFT-SAPT) values. The extent to which such
       comparison is meaningful is discussed. The comparability is shown to
       depend strongly on the intermolecular distance, which means that
       comparisons made at one distance only are of limited value. At large
       distances the coulombic and van der Waals 1/r(6) empirical terms
       correspond fairly well with the DFT-SAPT electrostatics and dispersion
       terms, respectively. At the onset of electronic overlap the empirical
       values deviate from the reference values considerably. However, the
       errors in the force fields tend to cancel out in a systematic manner at
       equilibrium distances. Thus, the overall performance of the force fields
       displays errors an order of magnitude smaller than those of the
       individual interaction energy components. The repulsive 1/r(12)
       component of the van der Waals expression seems to be responsible for a
       significant part of the deviation of the force field results from the
       reference values. We suggest that further improvement of the force
       fields for intermolecular interactions would require replacement of the
       nonphysical 1/r(12) term by an exponential function. Dispersion
       anisotropy and its effects are discussed. Our analysis is intended to
       show that although comparing the empirical and non-empirical interaction
       energy components is in general problematic, it might bring insights
       useful for the construction of new force fields. Our results are
       relevant to often performed force-field-based interaction energy
       decompositions.,
    DOI = 10.1039/c002656e,
    ISSN = 1463-9076,
    Unique-ID = ISI:000281352300043,
    

2009

  • [DOI] M. Pavlova, M. Klvana, Z. Prokop, R. Chaloupkova, P. Banas, M. Otyepka, R. C. Wade, M. Tsuda, Y. Nagata, and J. Damborsky, “Redesigning dehalogenase access tunnels as a strategy for degrading an
    anthropogenic substrate,” NATURE CHEMICAL BIOLOGY, vol. 5, iss. 10, pp. 727-733, 2009.
    [Bibtex]
    @article ISI:000270039900010,
    Author = Pavlova, Martina and Klvana, Martin and Prokop, Zbynek and Chaloupkova,
       Radka and Banas, Pavel and Otyepka, Michal and Wade, Rebecca C. and
       Tsuda, Masataka and Nagata, Yuji and Damborsky, Jiri,
    Title = Redesigning dehalogenase access tunnels as a strategy for degrading an
       anthropogenic substrate,
    Journal = NATURE CHEMICAL BIOLOGY,
    Year = 2009,
    Volume = 5,
    Number = 10,
    Pages = 727-733,
    Month = OCT,
    Abstract = Engineering enzymes to degrade anthropogenic compounds efficiently is
       challenging. We obtained Rhodococcus rhodochrous haloalkane dehalogenase
       mutants with up to 32-fold higher activity than wild type toward the
       toxic, recalcitrant anthropogenic compound 1,2,3-trichloropropane (TCP)
       using a new strategy. We identified key residues in access tunnels
       connecting the buried active site with bulk solvent by rational design
       and randomized them by directed evolution. The most active mutant has
       large aromatic residues at two out of three randomized positions and two
       positions modified by site-directed mutagenesis. These changes
       apparently enhance activity with TCP by decreasing accessibility of the
       active site for water molecules, thereby promoting activated complex
       formation. Kinetic analyses confirmed that the mutations improved
       carbon-halogen bond cleavage and shifted the rate-limiting step to the
       release of products. Engineering access tunnels by combining
       computer-assisted protein design with directed evolution may be a
       valuable strategy for refining catalytic properties of enzymes with
       buried active sites.,
    DOI = 10.1038/nchembio.205,
    ISSN = 1552-4450,
    Unique-ID = ISI:000270039900010,
    
  • [DOI] P. Banas, P. Jurecka, N. G. Walter, J. Sponer, and M. Otyepka, “Theoretical studies of RNA catalysis: Hybrid QM/MM methods and their
    comparison with MD and QM,” METHODS, vol. 49, iss. 2, pp. 202-216, 2009.
    [Bibtex]
    @article ISI:000270443600015,
    Author = Banas, Pavel and Jurecka, Petr and Walter, Nils G. and Sponer, Jiri and
       Otyepka, Michal,
    Title = Theoretical studies of RNA catalysis: Hybrid QM/MM methods and their
       comparison with MD and QM,
    Journal = METHODS,
    Year = 2009,
    Volume = 49,
    Number = 2,
    Pages = 202-216,
    Month = OCT,
    Abstract = Hybrid QM/MM methods combine the rigor of quantum mechanical (QM)
       calculations with the low computational cost of empirical molecular
       mechanical (MM) treatment allowing to capture dynamic properties to
       probe critical atomistic details of enzyme reactions. Catalysis by RNA
       enzymes (ribozymes) has only recently begun to be addressed with QM/MM
       approaches and is thus still a field under development. This review
       surveys methodology as well as recent advances in QM/MM applications to
       RNA mechanisms, including those of the HDV, hairpin, and hammerhead
       ribozymes, as well as the ribosome. We compare and correlate QM/MM
       results with those from QM and/or molecular dynamics (MD) simulations,
       and discuss scope and limitations with a critical eye on current
       shortcomings in available methodologies and computer resources. We thus
       hope to foster mutual appreciation and facilitate collaboration between
       experimentalists and theorists to jointly advance our understanding of
       RNA catalysis at an atomistic level. (c) 2009 Elsevier Inc. All rights
       reserved.,
    DOI = 10.1016/j.ymeth.2009.04.007,
    ISSN = 1046-2023,
    Unique-ID = ISI:000270443600015,
    
  • [DOI] M. Kubala, L. Grycova, Z. Lansky, P. Sklenovsky, M. Janovska, M. Otyepka, and J. Teisinger, “Changes in Electrostatic Surface Potential of Na(+)/K(+)-ATPase
    Cytoplasmic Headpiece Induced by Cytoplasmic Ligand(s) Binding,” BIOPHYSICAL JOURNAL, vol. 97, iss. 6, pp. 1756-1764, 2009.
    [Bibtex]
    @article ISI:000270380800027,
    Author = Kubala, Martin and Grycova, Lenka and Lansky, Zdenek and Sklenovsky,
       Petr and Janovska, Marika and Otyepka, Michal and Teisinger, Jan,
    Title = Changes in Electrostatic Surface Potential of Na(+)/K(+)-ATPase
       Cytoplasmic Headpiece Induced by Cytoplasmic Ligand(s) Binding,
    Journal = BIOPHYSICAL JOURNAL,
    Year = 2009,
    Volume = 97,
    Number = 6,
    Pages = 1756-1764,
    Month = SEP 16,
    Abstract = A set of single-tryptophan mutants of the Na(+)/K(+)-ATPase isolated,
       large cytoplasmic loop connecting transmembrane helices M4 and M5 (C45)
       was prepared to monitor effects of the natural cytoplasmic ligands
       (i.e., Mg(2+) and/or ATP) binding. We introduced a novel method for the
       monitoring of the changes in the electrostatic surface potential (ESP)
       induced by ligand binding, using the quenching of the intrinsic
       tryptophan fluorescence by acrylamide or iodide. This approach opens a
       new way to understanding the interactions within the proteins. Our
       experiments revealed that the C45 conformation in the presence of the
       ATP (without magnesium) substantially differed from the conformation in
       the presence of Mg(2+) or MgATP or in the absence of any ligand not only
       in the sense of geometry but also in the sense of the ESP. Notably, the
       set of ESP-sensitive residues was different from the set of
       geometry-sensitive residues. Moreover, our data indicate that the effect
       of the ligand binding is not restricted only to the close environment of
       the binding site and that the information is in fact transmitted also to
       the distal parts of the molecule. This property could be important for
       the communication between the cytoplasmic headpiece and the cation
       binding sites located within the transmembrane domain.,
    DOI = 10.1016/j.bpj.2009.07.002,
    ISSN = 0006-3495,
    Unique-ID = ISI:000270380800027,
    
  • P. Anzenbacher, E. Anzenbacherova, T. Hendrychova, M. Otyepka, J. Hudecek, P. Hildebrandt, and R. Lange, “Flexibility and plasticity of the structures of cytochromes P450 as a
    property determining their function,” FEBS JOURNAL, vol. 276, pp. 26, 2009.
    [Bibtex]
    @article ISI:000267069900070,
    Author = Anzenbacher, P. and Anzenbacherova, E. and Hendrychova, T. and Otyepka,
       M. and Hudecek, J. and Hildebrandt, P. and Lange, R.,
    Title = Flexibility and plasticity of the structures of cytochromes P450 as a
       property determining their function,
    Journal = FEBS JOURNAL,
    Year = 2009,
    Volume = 276,
    Pages = 26,
    Month = JUL,
    Note = 34th Congress of the Federation-of-European-Biochemical-Societies,
       Prague, CZECH REPUBLIC, JUL 04-09, 2009,
    Organization = Federat European Biochem Soc,
    ISSN = 1742-464X,
    Unique-ID = ISI:000267069900070,
    
  • P. Banas, N. G. Walter, J. Sponer, and M. Otyepka, “Structural Insight into RNA Catalysis Revealed by Molecular Dynamics
    Simulations and QM/MM Calculation,” JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, vol. 26, iss. 6, pp. 50, 2009.
    [Bibtex]
    @article ISI:000266300700062,
    Author = Banas, Pavel and Walter, Nils G. and Sponer, Jiri and Otyepka, Michal,
    Title = Structural Insight into RNA Catalysis Revealed by Molecular Dynamics
       Simulations and QM/MM Calculation,
    Journal = JOURNAL OF BIOMOLECULAR STRUCTURE \& DYNAMICS,
    Year = 2009,
    Volume = 26,
    Number = 6,
    Pages = 50,
    Month = JUN,
    ISSN = 0739-1102,
    Unique-ID = ISI:000266300700062,
    
  • [DOI] L. Grycova, P. Sklenovsk, Z. Lansky, M. Janovska, M. Otyepka, E. Amler, J. Teisinger, and M. Kubala, “ATP and magnesium drive conformational changes of the Na(+)/K(+)-ATPase
    cytoplasmic headpiece,” BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, vol. 1788, iss. 5, pp. 1081-1091, 2009.
    [Bibtex]
    @article ISI:000266190600019,
    Author = Grycova, Lenka and Sklenovsk, Petr and Lansky, Zdenek and Janovska,
       Marika and Otyepka, Michal and Amler, Evzen and Teisinger, Jan and
       Kubala, Martin,
    Title = ATP and magnesium drive conformational changes of the Na(+)/K(+)-ATPase
       cytoplasmic headpiece,
    Journal = BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES,
    Year = 2009,
    Volume = 1788,
    Number = 5,
    Pages = 1081-1091,
    Month = MAY,
    Abstract = Conformational changes of the Na(+)/K(+)-ATPase isolated large
       cytoplasmic segment connecting transmembrane helices M4 and M5 (C45)
       induced by the interaction with enzyme ligands (i.e. Mg(2+) and/or ATP)
       were investigated by means of the intrinsic tryptophan fluorescence
       measurement and molecular dynamic simulations. Our data revealed that
       this model system consisting of only two domains retained the ability to
       adopt open or closed conformation, i.e. behavior, which is expected from
       the crystal structures of relative Ca(2+)-ATPase from sarco(endo)plasmic
       reticulum for the corresponding part of the entire enzyme. Our data
       revealed that the C45 is found in the closed conformation in the absence
       of any ligand, in the presence of Mg(2+) only, or in the simultaneous
       presence of Mg(2+) and ATP. Binding of the ATP alone (i.e. in the
       absence of Mg(2+)) induced open conformation of the C45. The fact that
       the transmembrane part of the enzyme was absent in our experiments
       suggested that the observed conformational changes are consequences only
       of the interaction with ATP or Mg(2+) and may not be related to the
       transported cations binding/ release, as generally believed. Our data
       are consistent with the model, where ATP binding to the low-affinity
       site induces conformational change of the cytoplasmic part of the
       enzyme, traditionally attributed to E2 -> E1 transition, and subsequent
       Mg(2+) binding to the enzyme-ATP complex induces in turn conformational
       change traditionally attributed to E1 -> E2 transition. (C) 2009
       Elsevier B.V. All rights reserved.,
    DOI = 10.1016/j.bbamem.2009.02.004,
    ISSN = 0005-2736,
    Unique-ID = ISI:000266190600019,
    
  • [DOI] I. Besseova, M. Otyepka, K. Reblova, and J. Sponer, “Dependence of A-RNA simulations on the choice of the force field and
    salt strength,” PHYSICAL CHEMISTRY CHEMICAL PHYSICS, vol. 11, iss. 45, pp. 10701-10711, 2009.
    [Bibtex]
    @article ISI:000271907200016,
    Author = Besseova, Ivana and Otyepka, Michal and Reblova, Kamila and Sponer, Jiri,
    Title = Dependence of A-RNA simulations on the choice of the force field and
       salt strength,
    Journal = PHYSICAL CHEMISTRY CHEMICAL PHYSICS,
    Year = 2009,
    Volume = 11,
    Number = 45,
    Pages = 10701-10711,
    Abstract = We present an extensive molecular dynamics study (0.6 mu s in total) on
       three A-RNA duplexes. The dependence of the A-RNA geometry on force
       fields (Parm99 and Parmbsc0) and salt strength conditions (similar to
       0.18 M net-neutralizing Na(+) and similar to 0.3 M KCl) was
       investigated. The Parmbsc0 force field makes the A-RNA duplex more
       compact in comparison to the Parm99 by preventing temporary alpha/beta
       t/t flips common in Parm99 simulations. Nevertheless, since the
       alpha/gamma t/t sub-state occurs to certain extent in experimental A-RNA
       structures, we consider both force fields as viable. The stabilization
       of the A-RNA helices caused by the Parmbsc0 force field includes visible
       reduction of the major groove width, increase of the base pair roll,
       larger helical inclination and small increases of twist. Therefore, the
       Parmbsc0 shifts the simulated duplexes more deeply into the A-form.
       Further narrowing of the deep major groove is observed in excess salt
       simulations, again accompanied by larger roll, inclination and twist.
       The cumulative difference between Parm99/lower-salt and
       Parmbsc0/higher-salt simulations is similar to 4-8 angstrom for the
       average P center dot center dot center dot P distances, and -0.7 to -2.5
       degrees, -2.0 to -5.4 degrees, -2.6 to -8.6 degrees and 1.7 to 7.0
       degrees for the twist, roll, inclination and propeller, respectively.
       The effects of the force field and salt condition are
       sequence-dependent. Thus, the compactness of A-RNA is sensitive to the
       sequence and the salt strength which may, for example, modulate the
       end-to-end distance of the A-RNA helix. The simulations neatly reproduce
       the known base pair roll re-distribution in alternating
       purine-pyrimidine A-RNA helices.,
    DOI = 10.1039/b911169g,
    ISSN = 1463-9076,
    Unique-ID = ISI:000271907200016,
    

2008

  • [DOI] P. Banas, L. Rulisek, V. Hanosova, D. Svozil, N. G. Walter, J. Sponer, and M. Otyepka, “General base catalysis for cleavage by the active-site cytosine of the
    hepatitis delta virus ribozyme: QM/MM calculations establish chemical
    feasibility,” JOURNAL OF PHYSICAL CHEMISTRY B, vol. 112, iss. 35, pp. 11177-11187, 2008.
    [Bibtex]
    @article ISI:000258800300054,
    Author = Banas, Pavel and Rulisek, Lubomir and Hanosova, Veronika and Svozil,
       Daniel and Walter, Nils G. and Sponer, Jiri and Otyepka, Michal,
    Title = General base catalysis for cleavage by the active-site cytosine of the
       hepatitis delta virus ribozyme: QM/MM calculations establish chemical
       feasibility,
    Journal = JOURNAL OF PHYSICAL CHEMISTRY B,
    Year = 2008,
    Volume = 112,
    Number = 35,
    Pages = 11177-11187,
    Month = SEP 4,
    Abstract = The hepatitis delta virus (HDV) ribozyme is an RNA motif embedded in
       human pathogenic HDV RNA. Previous experimental studies have established
       that the active-site nucleotide C75 is essential for self-cleavage of
       the ribozyme, although its exact catalytic role in the process remains
       debated. Structural data from X-ray crystallography generally indicate
       that C75 acts as the general base that initiates catalysis by
       deprotonating the 2'-OH nucleophile at the cleavage site, while a
       hydrated magnesium ion likely protonates the 5'-oxygen leaving group. In
       contrast, some mechanistic studies support the role of C75 acting as
       general acid and thus being protonated before the reaction. We report
       combined quantum chemical/molecular mechanical calculations for the C75
       general base pathway, utilizing the available structural data for the
       wild type HDV genomic ribozyme as a starting point. Several starting
       configurations differing in magnesium ion placement were considered and
       both one-dimensional and two-dimensional potential energy surface scans
       were used to explore plausible reaction paths. Our calculations show
       that C75 is readily capable of acting as the general base, in concert
       with the hydrated magnesium ion as the general acid. We identify a most
       likely position for the magnesium ion, which also suggests it acts as a
       Lewis acid. The calculated energy barrier of the proposed mechanism,
       similar to 20 kcal/mol, would lower the reaction barrier by similar to
       15 kcal/mol compared with the uncatalyzed reaction and is in good
       agreement with experimental data.,
    DOI = 10.1021/jp802592z,
    ISSN = 1520-6106,
    Unique-ID = ISI:000258800300054,
    
  • [DOI] P. Sklenovsky, P. Banas, and M. Otyepka, “Two C-terminal ankyrin repeats form the minimal stable unit of the
    ankyrin repeat protein p18(INK4c),” JOURNAL OF MOLECULAR MODELING, vol. 14, iss. 8, pp. 747-759, 2008.
    [Bibtex]
    @article ISI:000257330700012,
    Author = Sklenovsky, Petr and Banas, Pavel and Otyepka, Michal,
    Title = Two C-terminal ankyrin repeats form the minimal stable unit of the
       ankyrin repeat protein p18(INK4c),
    Journal = JOURNAL OF MOLECULAR MODELING,
    Year = 2008,
    Volume = 14,
    Number = 8,
    Pages = 747-759,
    Month = AUG,
    Abstract = Ankyrin repeat proteins (ARPs) appear to be abundant in organisms from
       all phyla, and play critical regulatory roles, mediating specific
       interactions with target biomolecules and thus ordering the sequence of
       events in diverse cellular processes. ARPs possess a non-globular
       scaffold consisting of repeating motifs named ankyrin (ANK) repeats,
       which stack on each other. The modular architecture of ARPs provides a
       new paradigm for understanding protein stability and folding mechanisms.
       In the present study, the stability of various C-terminal fragments of
       the ARP p18(INK4c) was investigated by all-atomic 450 ns molecular
       dynamics (MD) simulations in explicit water solvent. Only motifs with at
       least two ANK repeats made stable systems in the available timescale.
       All smaller fragments were unstable, readily losing their native fold
       and alpha-helical content. Since each non-terminal ANK repeat has two
       hydrophobic sides, we may hypothesize that at least one hydrophobic side
       must be fully covered and shielded from the water as a necessary, but
       not sufficient, condition to maintain ANK repeat stability.
       Consequently, at least two ANK repeats are required to make a stable
       ARP.,
    DOI = 10.1007/s00894-008-0300-5,
    ISSN = 1610-2940,
    Unique-ID = ISI:000257330700012,
    
  • [DOI] I. Bartova, J. Koca, and M. Otyepka, “Regulatory phosphorylation of cyclin-dependent kinase 2: insights from
    molecular dynamics simulations,” JOURNAL OF MOLECULAR MODELING, vol. 14, iss. 8, pp. 761-768, 2008.
    [Bibtex]
    @article ISI:000257330700013,
    Author = Bartova, Iveta and Koca, Jaroslav and Otyepka, Michal,
    Title = Regulatory phosphorylation of cyclin-dependent kinase 2: insights from
       molecular dynamics simulations,
    Journal = JOURNAL OF MOLECULAR MODELING,
    Year = 2008,
    Volume = 14,
    Number = 8,
    Pages = 761-768,
    Month = AUG,
    Abstract = The structures of fully active cyclin-dependent kinase-2 (CDK2)
       complexed with ATP and peptide substrate, CDK2 after the catalytic
       reaction, and CDK2 inhibited by phosphorylation at Thr14/Tyr15 were
       studied using molecular dynamics (MD) simulations. The structural
       details of the CDK2 catalytic site and CDK2 substrate binding box were
       described. Comparison of MD simulations of inhibited complexes of CDK2
       was used to help understand the role of inhibitory phosphorylation at
       Thr14/Tyr15. Phosphorylation at Thr14/Tyr15 causes ATP misalignment for
       the phosphate-group transfer, changes in the Mg(2+)coordination sphere,
       and changes in the H-bond network formed by CDK2 catalytic residues
       (Asp127, Lys129, Asn132). The inhibitory phosphorylation causes the
       G-loop to shift from the ATP binding site, which leads to opening of the
       CDK2 substrate binding box, thus probably weakening substrate binding.
       All these effects explain the decrease in kinase activity observed after
       inhibitory phosphorylation at Thr14/Tyr15 in the G-loop. Interaction of
       the peptide substrate, and the phosphorylated peptide product, with CDK2
       was also studied and compared. These results broaden hypotheses drawn
       from our previous MD studies as to why a basic residue (Arg/Lys) is
       preferred at the P(+2) substrate position.,
    DOI = 10.1007/s00894-008-0312-1,
    ISSN = 1610-2940,
    Unique-ID = ISI:000257330700013,
    
  • [DOI] J. Skopalik, P. Anzenbacher, and M. Otyepka, “Flexibility of human cytochromes P450: Molecular dynamics reveals
    differences between CYPs 3A4, 2C9, and 2A6, which correlate with their
    substrate preferences,” JOURNAL OF PHYSICAL CHEMISTRY B, vol. 112, iss. 27, pp. 8165-8173, 2008.
    [Bibtex]
    @article ISI:000257335200028,
    Author = Skopalik, Josef and Anzenbacher, Pavel and Otyepka, Michal,
    Title = Flexibility of human cytochromes P450: Molecular dynamics reveals
       differences between CYPs 3A4, 2C9, and 2A6, which correlate with their
       substrate preferences,
    Journal = JOURNAL OF PHYSICAL CHEMISTRY B,
    Year = 2008,
    Volume = 112,
    Number = 27,
    Pages = 8165-8173,
    Month = JUL 10,
    Abstract = Molecular dynamics (MD) simulations at normal and high temperature were
       used to study the flexibility and malleability of three microsomal
       cytochromes P450 (CYPs): CYP3A4, CYP2C9, and CYP2A6. Comparison of
       B-factors (describing the atomic fluctuations) between X-ray and MD data
       shows that the X-ray B-factors are significantly lower in the regions
       where the crystal contacts occur than for other regions. Consequently,
       the conclusions about CYP flexibility based solely on the X-ray data
       might be misleading. Comparison of flexibility patterns of the three
       CYPs enabled common features and variations in flexibility and
       malleability of the studied CYPs to be identified. The previously
       described pattern of flexibility in topological elements of microsomal
       CYPs (a rigid heme binding core, a malleable distal side and
       intermediately flexible proximal side) was confirmed. These topological
       features provide an important combination of high stereo- and
       regio-specificity (mediated by the relative rigidity in the neighborhood
       of the heme), together with high substrate promiscuity due to the more
       flexible active site and the malleability of the distal side. The data
       acquired here show that the malleability of the three studied CYPs
       correlates with their substrate specificity: CYP2A6 has a narrow
       substrate range and is the most rigid, CYP3A4 is the most promiscuous
       CYP known and is the most malleable, and CYP2C9 is intermediate in terms
       of both its substrate specificity and malleability. Thus, the
       malleability of CYPs is probably a major determinant of their substrate
       specificity.,
    DOI = 10.1021/jp800311c,
    ISSN = 1520-6106,
    Unique-ID = ISI:000257335200028,
    
  • P. Dzubak, J. Sarek, P. Anzenbacher, V. Masek, P. Novak, V. Havlicek, M. Otyepka, D. Vydra, and M. Hajduch, “Betulinine JS8 induces apoptosis in tumor cells by mitochondrial
    disruption via specific non-covalent interactions with cytochrome c,” FEBS JOURNAL, vol. 275, iss. 1, pp. 447, 2008.
    [Bibtex]
    @article ISI:000256633301588,
    Author = Dzubak, P. and Sarek, J. and Anzenbacher, P. and Masek, V. and Novak, P.
       and Havlicek, V. and Otyepka, M. and Vydra, D. and Hajduch, M.,
    Title = Betulinine JS8 induces apoptosis in tumor cells by mitochondrial
       disruption via specific non-covalent interactions with cytochrome c,
    Journal = FEBS JOURNAL,
    Year = 2008,
    Volume = 275,
    Number = 1,
    Pages = 447,
    Month = JUN,
    Note = Joint Conference of the 33rd FEBS Congress/11th IUBMB Conference,
       Athens, GREECE, JUN 28-JUL 03, 2008,
    ISSN = 1742-464X,
    Unique-ID = ISI:000256633301588,
    
  • [DOI] M. Otyepka, P. Banas, A. Magistrato, P. Carloni, and J. Damborsky, “Second step of hydrolytic dehalogenation in haloalkane dehalogenase
    investigated by QM/MM methods,” PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, vol. 70, iss. 3, pp. 707-717, 2008.
    [Bibtex]
    @article ISI:000252836300009,
    Author = Otyepka, Michal and Banas, Pavel and Magistrato, Alessandra and Carloni,
       Paolo and Damborsky, Jiri,
    Title = Second step of hydrolytic dehalogenation in haloalkane dehalogenase
       investigated by QM/MM methods,
    Journal = PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS,
    Year = 2008,
    Volume = 70,
    Number = 3,
    Pages = 707-717,
    Month = FEB 15,
    Abstract = Mechanistic studies on the hydrolytic dehalogenation catalyzed by
       haloalkane dehalogenases are of importance for environmental and
       industrial applications. Here, Car-Parrinello (CP) and ONIOM hybrid
       quantum-mechanical/molecular mechanics (QM/MM) are used investigate the
       second reaction step of the catalytic cycle, which comprises a general
       base-catalyzed hydrolysis of an ester intermediate (EI) to alcohol and
       free enzyme. We focus on the enzyme LinB from Sphingo-monas paucimobilis
       UT26, for which the X-ray structure at atomic resolution is available.
       In agreement with previous proposals, our calculations suggest that a
       histidine residue (His272), polarized by glutamate (Glu132), acts as a
       base, accepting a proton from the catalytic water molecule and
       transferring it to an alcoholate ion. The reaction proceeds through a
       metastable tetrahedral intermediate, which shows an easily reversed
       reaction to the EI In the formation of the products, the protonated
       aspartic acid (Asp 108) can easily adopt conformation of the relaxed
       state found in the free enzyme. The overall free energy barrier of the
       reaction calculated by potential of the mean force integration using
       CP-QM/MM calculations is equal to 19.5 +/- 2 kcal . mol(-1). The
       lowering of the energy barrier of catalyzed reaction with respect to the
       water reaction is caused by strong stabilization of the reaction
       intermediate and transition state and their preorganization by
       electrostatic field of the enzyme.,
    DOI = 10.1002/prot.21523,
    ISSN = 0887-3585,
    Unique-ID = ISI:000252836300009,
    
  • P. Anzenbacher, E. Anzenbacherova, R. Lange, J. Skopalik, and M. Otyepka, “Active sites of cytochromes P450: What are they like?,” ACTA CHIMICA SLOVENICA, vol. 55, iss. 1, pp. 63-66, 2008.
    [Bibtex]
    @article ISI:000254379100008,
    Author = Anzenbacher, Pavel and Anzenbacherova, Eva and Lange, Reinhard and
       Skopalik, Josef and Otyepka, Michal,
    Title = Active sites of cytochromes P450: What are they like?,
    Journal = ACTA CHIMICA SLOVENICA,
    Year = 2008,
    Volume = 55,
    Number = 1,
    Pages = 63-66,
    Abstract = Although the x-ray crystallography is giving a relatively precise
       picture of spatial arrangement of the majority of protein structure, it
       is not able to give detailed information on the flexibility of the
       protein active site. The properties of active sites of cytochromes P450
       (CYP) were supposed earlier to be relatively similar, reflecting the
       substrate specificities of the individual enzymes mainly by the amino
       acid residues present in the respective active site. On the other hand,
       the most recent experimental as well as theoretical results document
       that it is the flexibility of this part of protein which gives the
       active site the property to bind substrates correctly and to accommodate
       them. It is also the flexibility or plasticity of the structure which
       determines or limits the property of the protein to keep the
       conformation which guarantees the function of the enzyme.,
    ISSN = 1318-0207,
    Unique-ID = ISI:000254379100008,
    
  • [DOI] I. Bartova, J. Koca, and M. Otyepka, “Functional flexibility of human cyclin-dependent kinase-2 and its
    evolutionary conservation,” PROTEIN SCIENCE, vol. 17, iss. 1, pp. 22-33, 2008.
    [Bibtex]
    @article ISI:000251834500004,
    Author = Bartova, Iveta and Koca, Jaroslav and Otyepka, Michal,
    Title = Functional flexibility of human cyclin-dependent kinase-2 and its
       evolutionary conservation,
    Journal = PROTEIN SCIENCE,
    Year = 2008,
    Volume = 17,
    Number = 1,
    Pages = 22-33,
    Month = JAN,
    Abstract = Cyclin-dependent kinase 2 (CDK2) is the most thoroughly studied of the
       cyclin-dependent kinases that regulate essential cellular processes,
       including the cell cycle, and it has become a model for studies of
       regulatory mechanisms at the molecular level. This contribution
       identifies flexible and rigid regions of CDK2 based on temperature
       B-factors acquired from both X-ray data and molecular dynamics
       simulations. In addition, the biological relevance of the identified
       flexible regions and their motions is explored using information from
       the essential dynamics analysis related to conformational changes of
       CDK2 and knowledge of its biological function(s). The conserved regions
       of CMGC protein kinases' primary sequences are located in the most rigid
       regions identified in our analyses, with the sole exception of the
       absolutely conserved G13 in the tip of the glycine-rich loop. The
       conserved rigid regions are important for nucleotide binding, catalysis,
       and substrate recognition. In contrast, the most flexible regions
       correlate with those where large conformational changes occur during
       CDK2 regulation processes. The rigid regions flank and form a rigid
       skeleton for the flexible regions, which appear to provide the
       plasticity required for CDK2 regulation. Unlike the rigid regions (which
       as mentioned are highly conserved) no evidence of evolutionary
       conservation was found for the flexible regions.,
    DOI = 10.1110/ps.072951208,
    ISSN = 0961-8368,
    Unique-ID = ISI:000251834500004,
    

2007

  • [DOI] M. Petrek, P. Kosinova, J. Koca, and M. Otyepka, “MOLE: A Voronoi diagram-based explorer of molecular channels, pores, and
    tunnels,” STRUCTURE, vol. 15, iss. 11, pp. 1357-1363, 2007.
    [Bibtex]
    @article ISI:000251023400007,
    Author = Petrek, Martin and Kosinova, Pavlina and Koca, Jaroslav and Otyepka,
       Michal,
    Title = MOLE: A Voronoi diagram-based explorer of molecular channels, pores, and
       tunnels,
    Journal = STRUCTURE,
    Year = 2007,
    Volume = 15,
    Number = 11,
    Pages = 1357-1363,
    Month = NOV,
    Abstract = We have developed an algorithm, ``MOLE,'' for the rapid, fully
       automated location and characterization of molecular channels, tunnels,
       and pores. This algorithm has been made freely available on the Internet
       (http://mole.chemi. muni.cz/) and overcomes many of the shortcomings and
       limitations of the recently developed CAVER software. The core of our
       MOLE algorithm is a Dijkstra's path search algorithm, which is applied
       to a Voronoi mesh. Tests on a wide variety of biomolecular systems
       including gramicidine, acetylcholinesterase, cytochromes P450, potassium
       channels, DNA quadruplexes, ribozymes, and the large ribosomal subunit
       have demonstrated that the MOLE algorithm performs well. MOLE is thus a
       powerful tool for exploring large molecular channels, complex networks
       of channels, and molecular dynamics trajectories in which analysis of a
       large number of snapshots is required.,
    DOI = 10.1016/j.str.2007.10.007,
    ISSN = 0969-2126,
    Unique-ID = ISI:000251023400007,
    
  • M. Kubala, L. Grycova, Z. Lansky, M. Otyepka, P. Sklenovsky, and J. Teisinger, “Conformational changes of the cytoplasmic part of Na+/K+-ATPase induced
    by the ligand binding,” FEBS JOURNAL, vol. 274, iss. 1, pp. 127, 2007.
    [Bibtex]
    @article ISI:000253283800335,
    Author = Kubala, M. and Grycova, L. and Lansky, Z. and Otyepka, M. and
       Sklenovsky, P. and Teisinger, J.,
    Title = Conformational changes of the cytoplasmic part of Na+/K+-ATPase induced
       by the ligand binding,
    Journal = FEBS JOURNAL,
    Year = 2007,
    Volume = 274,
    Number = 1,
    Pages = 127,
    Month = JUL,
    Note = 32nd Congress of the Federation-of-European-Biochemical-Societies
       (FEBS), Vienna, AUSTRIA, JUL 07-12, 2007,
    Organization = Federat European Biochem Soc,
    ISSN = 1742-464X,
    Unique-ID = ISI:000253283800335,
    
  • [DOI] J. Filip, R. Zboril, O. Schneeweiss, J. Zeman, M. Cernik, P. Kvapil, and M. Otyepka, “Environmental applications of chemically pure natural ferrihydrite,” ENVIRONMENTAL SCIENCE & TECHNOLOGY, vol. 41, iss. 12, pp. 4367-4374, 2007.
    [Bibtex]
    @article ISI:000247187600026,
    Author = Filip, Jan and Zboril, Radek and Schneeweiss, Oldrich and Zeman, Josef
       and Cernik, Miroslav and Kvapil, Petr and Otyepka, Michal,
    Title = Environmental applications of chemically pure natural ferrihydrite,
    Journal = ENVIRONMENTAL SCIENCE \& TECHNOLOGY,
    Year = 2007,
    Volume = 41,
    Number = 12,
    Pages = 4367-4374,
    Month = JUN 15,
    Abstract = Fresh precipitates, deposited from seepage waters of complex-ore
       mine-tailing impoundment at Zlate Hory, Czech Republic, were
       characterized by means of X-ray diffraction, transmission electron
       microscopy, low temperature and in-field Mossbauer spectroscopy, and
       Brunauer-Emmett-Teller surface area measurements. The prevailing phases
       (similar to 96 wt \%) found in precipitates are poorly crystalline, 2-6
       nm sized two-line ferrihydrite, forming globular aggregates of about 150
       nm in diameter, rimmed by acicular irregular nanocrystals of goethite.
       These nanocrystalline ferrihydrite-goethite precipitates are of a
       relatively high chemical purity (similar to 3\% SiO2, Zn similar to 1300
       ppm, trace and rare earth elements < 100 ppm) and thus applicable in
       various nanotechnologies. With a surface area of 270 m(2) g(-1),
       precipitate possesses a high catalytic activity in the decomposition of
       hydrogen peroxide, which is comparable with that found for commercially
       accessible FeO(OH) catalyst. Another superior aspect of such natural
       nanoparticles presents a cheap and suitable precursor for a thermally
       induced solid-state synthesis of the stable core-shell alpha-Fe-FeO
       nanoparticles that are well applicable in reductive technologies of
       groundwater treatment. Just the possibility of using the undesirable
       waste contaminating the environment in further environmental
       technologies is the key practical benefit discussed in this paper.,
    DOI = 10.1021/es062312t,
    ISSN = 0013-936X,
    Unique-ID = ISI:000247187600026,
    
  • [DOI] M. Otyepka, J. Skopalik, E. Anzenbacherova, and P. Anzenbacher, "What common structural features and variations of mammalian P450s are
    known to date?," BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, vol. 1770, iss. 3, pp. 376-389, 2007.
    [Bibtex]
    @article ISI:000244384800006,
    Author = Otyepka, Michal and Skopalik, Josef and Anzenbacherova, Eva and
       Anzenbacher, Pavel,
    Title = What common structural features and variations of mammalian P450s are
       known to date?,
    Journal = BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS,
    Year = 2007,
    Volume = 1770,
    Number = 3,
    Pages = 376-389,
    Month = MAR,
    Abstract = Sufficient structural information on mammalian cytochromes P450 has now
       been published (including seventeen X-ray structures of these enzymes by
       June 2006) to allow characteristic features of these enzymes to be
       identified, including: (i) the presence of a common fold, typical of all
       P450s, (ii) similarities in the positioning of the heme cofactor, (iii)
       the spatial arrangement of certain structural elements, and (iv) the
       access/egress paths for substrates and products, (v) probably common
       orientation in the membrane, (vi) characteristic properties of the
       active sites with networks of water molecules, (vii) mode of interaction
       with redox partners and (viii) a certain degree of flexibility of the
       structure and active site determining the ease with which the enzyme may
       bind the substrates. As well as facilitating the identification of
       common features, comparison of the available structures allows
       differences among the structures to be identified, including variations
       in: (i) preferred access/egress paths to/from the active site, (ii) the
       active site volume and (iii) flexible regions. The availability of
       crystal structures provides opportunities for molecular dynamic
       simulations, providing data that are apparently complementary to
       experimental findings but also allow the dynamic behavior of
       access/egress paths and other dynamic features of the enzymes to be
       explored. (c) 2006 Elsevier B.V. All rights reserved.,
    DOI = 10.1016/j.bbagen.2006.09.013,
    ISSN = 0304-4165,
    Unique-ID = ISI:000244384800006,
    

2006

  • [DOI] M. Petrek, M. Otyepka, P. Banas, P. Kosinova, J. Koca, and J. Damborsky, "CAVER: a new tool to explore routes from protein clefts, pockets and
    cavities," BMC BIOINFORMATICS, vol. 7, 2006.
    [Bibtex]
    @article ISI:000239737800001,
    Author = Petrek, Martin and Otyepka, Michal and Banas, Pavel and Kosinova,
       Pavlina and Koca, Jaroslav and Damborsky, Jiri,
    Title = CAVER: a new tool to explore routes from protein clefts, pockets and
       cavities,
    Journal = BMC BIOINFORMATICS,
    Year = 2006,
    Volume = 7,
    Month = JUN 22,
    Abstract = Background: The main aim of this study was to develop and implement an
       algorithm for the rapid, accurate and automated identification of paths
       leading from buried protein clefts, pockets and cavities in dynamic and
       static protein structures to the outside solvent.
       Results: The algorithm to perform a skeleton search was based on a
       reciprocal distance function grid that was developed and implemented for
       the CAVER program. The program identifies and visualizes routes from the
       interior of the protein to the bulk solvent. CAVER was primarily
       developed for proteins, but the algorithm is sufficiently robust to
       allow the analysis of any molecular system, including nucleic acids or
       inorganic material. Calculations can be performed using discrete
       structures from crystallographic analysis and NMR experiments as well as
       with trajectories from molecular dynamics simulations. The fully
       functional program is available as a stand-alone version and as plug-in
       for the molecular modeling program PyMol. Additionally, selected
       functions are accessible in an online version.
       Conclusion: The algorithm developed automatically finds the path from a
       starting point located within the interior of a protein. The algorithm
       is sufficiently rapid and robust to enable routine analysis of molecular
       dynamics trajectories containing thousands of snapshots. The algorithm
       is based on reciprocal metrics and provides an easy method to find a
       centerline, i.e. the spine, of complicated objects such as a protein
       tunnel. It can also be applied to many other molecules. CAVER is freely
       available from the web site http://loschmidt.chemi.muni.cz/caver/.,
    DOI = 10.1186/1471-2105-7-316,
    Article-Number = 316,
    ISSN = 1471-2105,
    Unique-ID = ISI:000239737800001,
    
  • [DOI] P. Banas, M. Otyepka, P. Jerabek, M. Petrek, and J. Damborsky, "Mechanism of enhanced conversion of 1,2,3-trichloropropane by mutant
    haloalkane dehalogenase revealed by molecular modeling," JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, vol. 20, iss. 6, pp. 375-383, 2006.
    [Bibtex]
    @article ISI:000241900000003,
    Author = Banas, Pavel and Otyepka, Michal and Jerabek, Petr and Petrek, Martin
       and Damborsky, Jiri,
    Title = Mechanism of enhanced conversion of 1,2,3-trichloropropane by mutant
       haloalkane dehalogenase revealed by molecular modeling,
    Journal = JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,
    Year = 2006,
    Volume = 20,
    Number = 6,
    Pages = 375-383,
    Month = JUN,
    Abstract = 1,2,3-Trichloropropane (TCP) is a highly toxic, recalcitrant byproduct
       of epichlorohydrin manufacture. Haloalkane dehalogenase (DhaA) from
       Rhodococcus sp. hydrolyses the carbon-halogen bond in various
       halogenated compounds including TCP, but with low efficiency (k(cat)/K-m
       = 36 s(-1)M(-1)). A Cys176Tyr-DhaA mutant with a threefold higher
       catalytic efficiency for TCP dehalogenation has been previously obtained
       by error-prone PCR. We have used molecular simulations and quantum
       mechanical calculations to elucidate the molecular mechanisms involved
       in the improved catalysis of the mutant, and enantioselectivity of DhaA
       toward TCP. The Cys176Tyr mutation modifies the protein access and
       export routes. Substitution of the Cys residue by the bulkier Tyr
       narrows the upper tunnel, making the second tunnel ``slot'' the
       preferred route. TCP can adopt two major orientations in the DhaA
       enzyme, in one of which the halide-stabilizing residue Asn41 forms a
       hydrogen bond with the terminal halogen atom of the TCP molecule, while
       in the other it bonds with the central halogen atom. The differences in
       these binding patterns explain the preferential formation of the (R)-
       over the (S)-enantiomer of 2,3-dichloropropane-1-ol in the reaction
       catalyzed by the enzyme.,
    DOI = 10.1007/s10822-006-9071-1,
    ISSN = 0920-654X,
    Unique-ID = ISI:000241900000003,
    
  • [DOI] P. Dobes, M. Otyepka, M. Strnad, and P. Hobza, "Interaction energies for the purine inhibitor roscovitine with
    cyclin-dependent kinase 2: Correlated ab initio quantum-chemical, DFT
    and empirical calculations," CHEMISTRY-A EUROPEAN JOURNAL, vol. 12, iss. 16, pp. 4297-4304, 2006.
    [Bibtex]
    @article ISI:000238032400009,
    Author = Dobes, P and Otyepka, M and Strnad, M and Hobza, P,
    Title = Interaction energies for the purine inhibitor roscovitine with
       cyclin-dependent kinase 2: Correlated ab initio quantum-chemical, DFT
       and empirical calculations,
    Journal = CHEMISTRY-A EUROPEAN JOURNAL,
    Year = 2006,
    Volume = 12,
    Number = 16,
    Pages = 4297-4304,
    Month = MAY 24,
    Abstract = The interaction between roscovitine and cyclin-dependent kinase 2 (cdk2)
       was investigated by performing correlated ab initio quantum-chemical
       calculations. The whole protein was fragmented into smaller systems
       consisting of one or a few amino acids, and the interaction energies of
       these fragments with roscovitine were determined by using the MP2 method
       with the extended aug-cc-pVDZ basis set. For selected complexes, the
       complete basis set limit MP2 interaction energies, as well as the
       coupled-cluster corrections with inclusion of single, double and
       noninteractive triples contributions [CCSD(T)], were also evaluated.
       The energies of interaction between roscovitine and small fragments and
       between roscovitine and substantial sections of protein (722 atoms) were
       also computed by using density-functional tight-binding methods covering
       dispersion energy (DFTB-D) and the Cornell empirical potential. Total
       stabilisation energy originates predominantly from dispersion energy and
       methods that do not account for the dispersion energy cannot, therefore,
       be recommended for the study of protein-inhibitor interactions. The
       Cornell empirical potential describes reasonably well the interaction
       between roscovitine and protein; therefore, this method can be applied
       in future thermodynamic calculations. A limited number of amino acid
       residues contribute significantly to the binding of roscovitine and
       cdk2, whereas a rather large number of amino acids make a negligible
       contribution.,
    DOI = 10.1002/chem.200501269,
    ISSN = 0947-6539,
    Unique-ID = ISI:000238032400009,
    
  • [DOI] M. Otyepka, I. Bartova, Z. Kriz, and J. Koca, "Different mechanisms of CDK5 and CDK2 activation as revealed by CDK5/p25
    and CDK2/cyclin A dynamics," JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 281, iss. 11, pp. 7271-7281, 2006.
    [Bibtex]
    @article ISI:000236030900045,
    Author = Otyepka, M and Bartova, I and Kriz, Z and Koca, J,
    Title = Different mechanisms of CDK5 and CDK2 activation as revealed by CDK5/p25
       and CDK2/cyclin A dynamics,
    Journal = JOURNAL OF BIOLOGICAL CHEMISTRY,
    Year = 2006,
    Volume = 281,
    Number = 11,
    Pages = 7271-7281,
    Month = MAR 17,
    Abstract = A detailed analysis is presented of the dynamics of human CDK5 in
       complexes with the protein activator p25 and the purine-like inhibitor
       roscovitine. These and other findings related to the activation of CDK5
       are critically reviewed from a molecular perspective. In addition, the
       results obtained on the behavior of CDK5 are compared with data on CDK2
       to assess the differences and similarities between the two kinases in
       terms of (i) roscovitine binding, (ii) regulatory subunit association,
       (iii) conformational changes in the T-loop following CDK/regulatory
       subunit complex formation, and (iv) specificity in CDK/regulatory
       subunit recognition. An energy decomposition analysis, used for these
       purposes, revealed why the binding of p25 alone is sufficient to
       stabilize the extended active T-loop conformation of CDK5, whereas the
       equivalent conformational change in CDK2 requires both the binding of
       cyclin A and phosphorylation of the Thr(160) residue. The interaction
       energy of the CDK5 T-loop with p25 is about 26 kcal . mol(-1) greater
       than that of the CDK2T-loop with cyclin A. The binding pattern between
       CDK5 and p25 was compared with that of CDK2/cyclin A to find specific
       regions involved in CDK/regulatory subunit recognition. The analyses
       performed revealed that the alpha NT-helix of cyclin A interacts with
       the alpha 6-alpha 7 loop and the alpha 7 helix of CDK2, but these
       regions do not interact in the CDK5/p25 complex. Further differences
       between the CDK5/p25 and CDK2/cyclin A systems studied are discussed
       with respect to their specific functionality.,
    DOI = 10.1074/jbc.M509699200,
    ISSN = 0021-9258,
    Unique-ID = ISI:000236030900045,
    
  • [DOI] M. Otyepka, P. Sklenovsky, D. Horinek, T. Kubar, and P. Hobza, "How the stabilization of INK4 tumor suppressor 3D structure evaluated by
    quantum chemical and molecular mechanics calculations corresponds well
    with experimental results: Interplay of association enthalpy, entropy,
    and solvation effects," JOURNAL OF PHYSICAL CHEMISTRY B, vol. 110, iss. 9, pp. 4423-4429, 2006.
    [Bibtex]
    @article ISI:000235944500084,
    Author = Otyepka, M and Sklenovsky, P and Horinek, D and Kubar, T and Hobza, P,
    Title = How the stabilization of INK4 tumor suppressor 3D structure evaluated by
       quantum chemical and molecular mechanics calculations corresponds well
       with experimental results: Interplay of association enthalpy, entropy,
       and solvation effects,
    Journal = JOURNAL OF PHYSICAL CHEMISTRY B,
    Year = 2006,
    Volume = 110,
    Number = 9,
    Pages = 4423-4429,
    Month = MAR 9,
    Abstract = The folding free energy of the INK4c tumor suppressor core, consisting
       of 10 helices, was determined as the sum of gas-phase interaction
       enthalpy, gas-phase interaction entropy, and dehydration and hydration
       free energy. The interaction energy and the hydration free energy were
       determined using the nonempirical density functional theory (DFT)
       method, augmented by a dispersion-energy correction term, the
       semiempirical density-functional tight-binding method covering the
       dispersion energy, and the density functional theory/conductor-like
       screening model (DFT/COSMO) procedure, whereas the interaction entropy
       was calculated with the empirical Cornell et al. force field.
       Alternatively, all contributions were evaluated consistently using
       empirical methods. All the values of the interaction energy of helix
       pairs are stabilizing, and the dominant stabilizing terms stem from the
       London dispersion energy and, in the case of charged systems, the
       electrostatic energy. The stabilization energy of the core, determined
       as the difference of the energy of the core and 10 separate helices,
       amounts to similar to 450 kcal/mol. Systematically, the difference in
       the hydration free energy of a helix pair and its separate components is
       smaller in magnitude than the interaction energy, and it is negative for
       some pairs while positive for others. The average total free energy of a
       core formation amounts to -29.6 kcal/mol (yielded by scaled
       quantum-chemical methods) and + 13.9 kcal/mol (resulting from empirical
       methods). These values are considerably smaller than their single
       components, which are dominated by the interaction energy. The
       computationally predicted interval encloses the experimental value of
       the folding free energy (-2.8 kcal/mol).,
    DOI = 10.1021/jp056890s,
    ISSN = 1520-6106,
    Unique-ID = ISI:000235944500084,
    

2005

  • [DOI] I. Bartova, M. Otyepka, Z. Kriz, and J. Koca, "The mechanism of inhibition of the cyclin-dependent kinase-2 as revealed
    by the molecular dynamics study on the complex CDK2 with the peptide
    substrate HHASPRK," PROTEIN SCIENCE, vol. 14, iss. 2, pp. 445-451, 2005.
    [Bibtex]
    @article ISI:000226626000019,
    Author = Bartova, I and Otyepka, M and Kriz, Z and Koca, J,
    Title = The mechanism of inhibition of the cyclin-dependent kinase-2 as revealed
       by the molecular dynamics study on the complex CDK2 with the peptide
       substrate HHASPRK,
    Journal = PROTEIN SCIENCE,
    Year = 2005,
    Volume = 14,
    Number = 2,
    Pages = 445-451,
    Month = FEB,
    Abstract = Molecular dynamics (MD) simulations were used to explain structural
       details of cyclin-dependent kinaSe-2 (CDK2) inhibition by
       phosphorylation at T14 and/or Y15 located in the glycine-rich loop
       (G-loop). Ten-nanosecond-long simulations of fully active CDK2 in a
       complex with a short peptide (HHASPRK) Substrate and of CDK2 inhibited
       by phosphorylation of T14 and/or Y15 were produced. The inhibitory
       phosphorylations at T14 and/or Y15 show namely an ATP misalignment and a
       G-loop shift (similar to5 Angstrom) causing the opening of the substrate
       binding box. The biological functions of the G-loop and GxGxxG inotif
       evolutionary conservation in protein kinases are discussed. The position
       of the ATP gamma-phosphate relative to the phosphorylation site (S/T) of
       the peptide substrate in the active CDK2 is described and compared with
       inhibited forms of CDK2. The MID results clearly provide an explanation
       previously not known as to why a basic residue (R/K) is preferred at the
       P, position in phosphorylated S/T peptide substrates.,
    DOI = 10.1110/ps.04959705,
    ISSN = 0961-8368,
    Unique-ID = ISI:000226626000019,
    

2004

  • [DOI] I. Bartova, M. Otyepka, Z. Kriz, and J. Koca, "Activation and inhibition of cyclin-dependent kinase-2 by
    phosphorylation; a molecular dynamics study reveals the functional
    importance of the glycine-rich loop," PROTEIN SCIENCE, vol. 13, iss. 6, pp. 1449-1457, 2004.
    [Bibtex]
    @article ISI:000221630900002,
    Author = Bartova, I and Otyepka, M and Kriz, Z and Koca, J,
    Title = Activation and inhibition of cyclin-dependent kinase-2 by
       phosphorylation; a molecular dynamics study reveals the functional
       importance of the glycine-rich loop,
    Journal = PROTEIN SCIENCE,
    Year = 2004,
    Volume = 13,
    Number = 6,
    Pages = 1449-1457,
    Month = JUN,
    Abstract = Nanoseconds long molecular dynamics (MD) trajectories of differently
       active complexes of human cyclin-dependent kinase 2 (inactive CDK2/ATP,
       semiactive CDK2/Cyclin A/ATP, fully active pT160-CDK2/Cyclin A/ATP,
       inhibited pT14-; pY15-; and pT14,pY15,pT160-CDK2/Cyclin A/ATP) were
       compared. The MD simulations results of CDK2 inhibition by
       phosphorylation at T14 and/or Y15 sites provide insight into the
       structural aspects of CDK2 deactivation. The inhibitory sites are
       localized in the glycine-rich loop (G-loop) positioned opposite the
       activation T-loop. Phosphorylation of T14 and both inhibitory sites T14
       and Y15 together causes ATP misalignment for phosphorylation and G-loop
       conformational change. This conformational change leads to the opening
       of the CDK2 Substrate binding box. The phosphorylated Y15 residue
       negatively affects Substrate binding or its correct alignment for ATP
       terminal phospho-group transfer to the CDK2 substrate. The MD
       simulations of the CDK2 activation process provide results in agreement
       with previous X-ray data.,
    DOI = 10.1110/ps.03578504,
    ISSN = 0961-8368,
    Unique-ID = ISI:000221630900002,
    
  • [DOI] Z. Kriz, M. Otyepka, I. Bartova, and J. Koca, "Analysis of CDK2 active-site hydration: A method to design new
    inhibitors," PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, vol. 55, iss. 2, pp. 258-274, 2004.
    [Bibtex]
    @article ISI:000220980600007,
    Author = Kriz, Z and Otyepka, M and Bartova, I and Koca, J,
    Title = Analysis of CDK2 active-site hydration: A method to design new
       inhibitors,
    Journal = PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS,
    Year = 2004,
    Volume = 55,
    Number = 2,
    Pages = 258-274,
    Month = MAY 1,
    Abstract = The interactions between the protein and the solvent were analyzed, and
       protein regions with a high density of water molecules, as well as
       structural water molecules, were determined by using molecular dynamics
       (MD) simulations. A number of water molecules that were in contact with
       the protein for the whole trajectory were determined. Their interaction
       energies and hydrogen bonds with protein residues were analyzed.
       Altogether, 39, 27, 49, and 32 water molecules bound to the protein were
       found for trajectories of the free CDK2, CDK2/ATP, CDK2/roscovitine, and
       CDK2/isopentenyladenine complexes, respectively. Positions of observed
       water molecules were compared with X-ray crystallography data. Special
       attention was paid to water molecules in the active site of the enzyme,
       and especially to the deep pocket, where the N9 roscovitine side-chain
       is buried. Exchange of active-site water molecules with bulk water
       through the tunnel from the pocket was observed. In the
       CDK2/isopentenyladenine complex simulation, two water molecules that
       arrange interaction between the inhibitor and the enzyme via an H-bond
       were observed. Two stable water molecules in the trajectory of the free
       CDK2 were found that occupy the same position as the nitrogens N3 and N9
       of the isopentenyladenine or N1 and N6 nitrogens of the adenosine
       triphosphate (ATP). The positions of structural water molecules were
       compared with the positions of substrate polar groups and
       crystallographic water molecules found in the Brookhaven Protein Data
       Bank for various CDK2 complexes. It was concluded that tracing tightly
       bound water molecules may substantially help in designing new
       inhibitors. (C) 2004 Wiley-Liss, Inc.,
    DOI = 10.1002/prot.20026,
    ISSN = 0887-3585,
    Unique-ID = ISI:000220980600007,
    
  • [DOI] A. Oakley, M. Klvana, M. Otyepka, Y. Nagata, M. Wilce, and J. Damborsky, "Crystal structure of haloalkane dehalogenase LinB from Sphingomonas
    paucimobilis UT26 at 0.95 angstrom resolution: Dynamics of catalytic
    residues," BIOCHEMISTRY, vol. 43, iss. 4, pp. 870-878, 2004.
    [Bibtex]
    @article ISI:000188504800005,
    Author = Oakley, AJ and Klvana, M and Otyepka, M and Nagata, Y and Wilce, MCJ and
       Damborsky, J,
    Title = Crystal structure of haloalkane dehalogenase LinB from Sphingomonas
       paucimobilis UT26 at 0.95 angstrom resolution: Dynamics of catalytic
       residues,
    Journal = BIOCHEMISTRY,
    Year = 2004,
    Volume = 43,
    Number = 4,
    Pages = 870-878,
    Month = FEB 3,
    Abstract = We present the structure of LinB, a 33-kDa haloalkane dehalogenase from
       Sphingomonas paucimobilis UT26, at 0.95 Angstrom resolution. The data
       have allowed us to directly observe the anisotropic motions of the
       catalytic residues. In particular, the side-chain of the catalytic
       nucleophile, Asp 108, displays a high degree of disorder. It has been
       modeled in two conformations, one similar to that observed previously
       (conformation A) and one strained (conformation 13) that approached the
       catalytic base (His272). The strain in conformation B was mainly in the
       C-alpha-C-beta-C-gamma angle (126degrees) that deviated by 13.4degrees
       from the ``ideal'' bond angle of 112.6degrees. On the basis of these
       observations, we propose a role for the charge state of the catalytic
       histidine in determining the geometry of the catalytic residues. We
       hypothesized that double-protonation of the catalytic base (His272)
       reduces the distance between the side-chain of this residue and that of
       the Asp108. The results of molecular dynamics simulations were
       consistent with the structural data showing that protonation of the
       His272 side-chain nitrogen atoms does indeed reduce the distance between
       the side-chains of the residues in question, although the simulations
       failed to demonstrate the same degree of strain in the Asp 108
       C-alpha-C-beta-C-gamma angle. Instead, the changes in the molecular
       dynamics structures were distributed over several bond and dihedral
       angles. Quantum mechanics calculations on Linl3 with
       1-chloro-2,2-dimethylpropane as a substrate were performed to determine
       which active site conformations and protonation states were most likely
       to result in catalysis. It was shown that His272 singly protonated at
       N-delta1 and Asp108 in conformation A gave the most exothermic reaction
       (DeltaH = -22 kcal/mol). With His272 doubly protonated at N-delta1 and
       N-epsilon2, the reactions were only slightly exothermic or were
       endothermic. In all calculations starting with Asp108 in conformation B,
       the Asp108 C-alpha-C-beta-C-gamma angle changed during the reaction and
       the Asp108 moved to conformation A. The results presented here indicate
       that the positions of the catalytic residues and charge state of the
       catalytic base are important for determining reaction energetics in
       LinB.,
    DOI = 10.1021/bi034748g,
    ISSN = 0006-2960,
    Unique-ID = ISI:000188504800005,
    

2003

  • [DOI] O. Pytela, M. Otyepka, J. Kulhanek, E. Otyepkova, and T. Nevecna, "Correlation of dissociation constants of 2-and 2,6-substituted anilines
    in water by methods based on the similarity principle and
    quantum-chemistry calculations," JOURNAL OF PHYSICAL CHEMISTRY A, vol. 107, iss. 51, pp. 11489-11496, 2003.
    [Bibtex]
    @article ISI:000187446900028,
    Author = Pytela, O and Otyepka, M and Kulhanek, J and Otyepkova, E and Nevecna, T,
    Title = Correlation of dissociation constants of 2-and 2,6-substituted anilines
       in water by methods based on the similarity principle and
       quantum-chemistry calculations,
    Journal = JOURNAL OF PHYSICAL CHEMISTRY A,
    Year = 2003,
    Volume = 107,
    Number = 51,
    Pages = 11489-11496,
    Month = DEC 25,
    Abstract = In the context of studies of the ortho effect, two series of
       2-monosubstituted (H, CH3, CF3, OH, CH3O, F, Cl, NH2, CN, NO2) and
       2,6-disubstituted anilines (containing all combinations of CH3, CH3O,
       Cl, and NO2 substituents) were chosen for this work. Commercially
       unavailable derivatives were synthesized, and dissociation constants in
       water were determined for those substances for which the proper
       measurements had not yet been carried out. A critical compilation of
       pK(a) literature data has been summarized and compared with the authors'
       own data. The analysis and interpretation of the ortho substitution
       effect and its manifestation in the dissociation constants of the
       studied anilines (as log K,,) was based on two different
       approaches-correlation analysis (similarity principle) and
       quantum-chemistry calculations. The classical correlation equation with
       substituent constants sigma(1) and sigmaR was extended by the parameter
       v describing the steric effects, but the correlation was not close
       enough (s = 0.514, R = 0.986). The AISE theory (alternative
       interpretation of substituent effects), extended by parameter v for the
       steric effects description, significantly improved the correlation (s =
       0.139, R = 0.9991). The B3LYP/6-311G(d,p) method was used for the
       calculation of physical-chemical properties of protonated and
       nonprotonated forms of aniline derivatives. Quantum chemically
       calculated properties were correlated with experimental data. The data
       mining regression method showed that the statistically most suitable
       interpreting variables are the Gibbs energy of the dissociation
       equilibrium (DeltaG(eq)) and the sum of the natural charges of the
       nonprotonated amino group hydrogen atoms (Q(n)(SigmaH)) and the dipole
       moment of the aniline protonated form (mu(+)). This correlation is
       closer (s = 0.316, R = 0.995) than that based on the similarity
       principle. The correlation with quantum-chemical characteristics
       indicates a close interrelation of the dissociation constant with the
       energy of the equilibrium participants and the delocalization energy of
       the nonprotonated form of aniline. The meaning of the SigmaH quantity in
       the correlation relation is related to the presence of a nitro
       substituent (intramolecular hydrogen bond with the reaction center). The
       dipole moment of the aniline protonated form mu(+) is in relation with
       nonspecific solvation in an aqueous medium.,
    DOI = 10.1021/jp022664w,
    ISSN = 1089-5639,
    Unique-ID = ISI:000187446900028,
    
  • [DOI] J. Moravec, V. Krystof, J. Hanus, L. Havlicek, D. Moravcova, K. Fuksova, M. Kuzma, R. Lenobel, M. Otyepka, and M. Strnad, "2,6,8,9-tetrasubstituted purines as new CDK1 inhibitors," BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 13, iss. 18, pp. 2993-2996, 2003.
    [Bibtex]
    @article ISI:000185221400010,
    Author = Moravec, J and Krystof, V and Hanus, J and Havlicek, L and Moravcova, D
       and Fuksova, K and Kuzma, M and Lenobel, R and Otyepka, M and Strnad, M,
    Title = 2,6,8,9-tetrasubstituted purines as new CDK1 inhibitors,
    Journal = BIOORGANIC \& MEDICINAL CHEMISTRY LETTERS,
    Year = 2003,
    Volume = 13,
    Number = 18,
    Pages = 2993-2996,
    Month = SEP 15,
    Abstract = Purine inhibitors of cyclin-dependent kinases attract attention as
       potential anticancer drugs because their first representative
       roscovitine recently entered clinical trials. Although well described in
       terms of structure-activity relationships, we still present here a novel
       modification of the purine scaffold influencing their inhibitory
       properties. The introduced C-8 substituents, however, lowered the CDK
       inhibitory activity of roscovitine, whereas the antiproliferative
       potential of several derivatives remained high. (C) 2003 Elsevier Ltd.
       All rights reserved.,
    DOI = 10.1016/S0960-894X(03)00632-2,
    ISSN = 0960-894X,
    Unique-ID = ISI:000185221400010,
    
  • I. Wiedermannova, M. Otyepka, J. Styskala, and J. Slouka, "The synthesis of some polycyclic N-H acids with quinoxaline and
    [1,2,4]triazines," ARKIVOC, iss. Part 15, pp. 65-74, 2003.
    [Bibtex]
    @article ISI:000220561700008,
    Author = Wiedermannova, I and Otyepka, M and Styskala, J and Slouka, J,
    Title = The synthesis of some polycyclic N-H acids with quinoxaline and
       [1,2,4]triazines,
    Journal = ARKIVOC,
    Year = 2003,
    Number = Part 15,
    Pages = 65-74,
    Abstract = 3-(4-Aminophenyl)-1,2-dihydro-quinoxaline-2-one (2b),
       3-(2-aminophenyl)-6,7-dimethyl-1,2-dihydro-quinoxaline-2-one (1b), its
       3-(4-aminophenyl)-isomer (3b),
       3-(2-aminobenzyl)-1,2-dihydro-quinoxaline-2-one (4b), its
       3-(4-aminobenzyl)-isomer (6b),
       3-(2-aminobenzyl)-6,7-dimethyl-1,2-dihydro-quinoxaline-2-one (5b) and
       its 3-(4-aminobenzyl)-isomer (7b) were diazotised and the resulting
       diazonium salts were coupled with ethyl cyanoacetylcarbamate,
       3-methyl-1,2-dihydro-quinoxaline-2-one,
       3,6,7-trimethyl-1,2-dihydro-quinoxaline-2-one and
       3-methyl-6,7-dichloro-1,2-dihydro-quinoxaline-2-one. In this manner the
       corresponding hydrazones with one 1,2-dihydro-quinoxaline-2-one ring
       (1d, 3d, 5d, 7d) and hydrazones with two 1,2-dihydro-quinoxaline-2-one
       rings (3e-3g, 4e-4g, 5e-5g, 6e-6g, 7e-7g) were obtained. Cyclization of
       hydrazones (1d, 3d, 5d, 7d) afforded compounds (1h, 3h, 5h, 7h)
       containing 6-azauracil and also 1,2-dihydroquinoxaline-2-one rings. The
       starting amino derivative (1b) was prepared by the reaction of
       N-acetylisatine with 4,5-dimethyl-o-phenylenediamine followed by
       hydrolysis of the N-acetyl derivative. The amino derivative (5b) was
       prepared by the condensation of 2-nitrophenylpyruvic acid with
       4,5-dimethyl-o-phenylenediamine and by reduction of the formed nitro
       derivative (5a). The amino derivative (3b) was prepared by the
       condensation of 4-acetylaminophenylglyoxylic acid with
       4,5-dimethyl-o-phenylenediamine and hydrolysis of the N-acetyl
       derivative. The amino derivative (7b) resulted from the condensation of
       4,5-dimethyl-o-phenylenediamine with 4-aminophenylpyruvic acid.,
    Unique-ID = ISI:000220561700008,
    

2002

  • M. Otyepka, Z. Kriz, and J. Koca, "Dynamics and binding modes of free cdk2 and its two complexes with
    inhibitors studied by computer simulations," JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, vol. 20, iss. 2, pp. 141-154, 2002.
    [Bibtex]
    @article ISI:000179043800001,
    Author = Otyepka, M and Kriz, Z and Koca, J,
    Title = Dynamics and binding modes of free cdk2 and its two complexes with
       inhibitors studied by computer simulations,
    Journal = JOURNAL OF BIOMOLECULAR STRUCTURE \& DYNAMICS,
    Year = 2002,
    Volume = 20,
    Number = 2,
    Pages = 141-154,
    Month = OCT,
    Abstract = This article presents a molecular dynamics (MD) study of the cdk2 enzyme
       and its two complexes with the inhibitors isopentenyladenine and
       roscovitine using the Cornell et at. force field from the AMBER software
       package. The results show that inserting an inhibitor into the enzyme
       active site does not considerably change enzyme structure but it
       seemingly changes the distribution of internal motions. The inhibitor
       causes differences in the domain motions in free cdk2 and in its
       complexes. It was found out that repulsion of roscovitine N9 substituent
       causes conformational change on Lys 33 side chain. Isopentenyladenine
       forms with Lys 33 side chain terminal amino group a hydrogen bond. It
       implies that the cavity, where N9 substituent of roscovitine is buried,
       can adopt larger substituent due to Lys 33 side chain flexibility. The
       composition of electrostatic and van der Waals interactions between the
       inhibitor and the enzyme were also calculated along both cdk2/inhibitor
       MD trajectories together with MM-PB/GBSA analysis. These results show
       that isopentenyladenine-like inhibitors could be more effective after
       modifications leading to an increase in their van der Waals contact with
       the enzyme. We suggest that a way leading to better inhibitors occupying
       isopentenyladenine binding mode could be: to keep N9 and N7 purine
       positions free, to keep 3,3-dimethylallylamino group at C6 position, and
       to add, e.g., benzylamino group at C2 position. The results support the
       idea that the isopentenyl adenine binding mode can be used for cdk2
       inhibitors design and that all possibilities to improve this binding
       mode were not uncovered yet.,
    ISSN = 0739-1102,
    Unique-ID = ISI:000179043800001,
    
  • [DOI] M. Otyepka and J. Damborsky, "Functionally relevant motions of haloalkane dehalogenases occur in the
    specificity-modulating cap domains," PROTEIN SCIENCE, vol. 11, iss. 5, pp. 1206-1217, 2002.
    [Bibtex]
    @article ISI:000175141900021,
    Author = Otyepka, M and Damborsky, J,
    Title = Functionally relevant motions of haloalkane dehalogenases occur in the
       specificity-modulating cap domains,
    Journal = PROTEIN SCIENCE,
    Year = 2002,
    Volume = 11,
    Number = 5,
    Pages = 1206-1217,
    Month = MAY,
    Abstract = One-nanosecond molecular dynamics trajectories of three haloalkane
       dehalogenases (Dh1A. LinB. and DhaA) are compared. The main domain was
       rigid in all three dehalogenases, whereas the substrate
       specificity-modulating cap domains showed considerably higher mobility.
       The functionally relevant motions were spread over the entire cap domain
       in Dh1A, whereas they were more localized in LinB and DhaA. The highest
       amplitude of essential motions of Dh1A was noted in the
       alpha4'-helix-loop-alpha4-helix region, formerly proposed to participate
       in the large conformation change needed for product release. The highest
       amplitude of essential motions of LinB and DhaA was observed in the
       random coil before helix 4, linking two domains of these proteins. This
       flexibility is the consequence of the modular composition of haloalkane
       dehalogenases. Two members of the catalytic triad. that is, the
       nucleophile and the base, showed a very high level of rigidity in all
       three dehalogenases. This rigidity is essential for their function. One
       of the halide-stabilizing residues, important for the catalysis, shows
       significantly higher flexibility in Dh1A compared with LinB and DhaA.
       Enhanced flexibility may be required for destabilization of the
       electrostatic interactions during the release of the halide ion from the
       deeply buried active site of Dh1A. The exchange of water molecules
       between the enzyme active site and bulk solvent was very different among
       the three dehalogenases. The differences could be related to the
       flexibility of the cap domains and to the number of entrance tunnels.,
    DOI = 10.1110/ps3830102,
    ISSN = 0961-8368,
    Unique-ID = ISI:000175141900021,
    

2000

  • [DOI] M. Otyepka, V. Krystof, L. Havlicek, V. Siglerova, M. Strnad, and J. Koca, "Docking-based development of purine-like inhibitors of cyclin-dependent
    kinase-2," JOURNAL OF MEDICINAL CHEMISTRY, vol. 43, iss. 13, pp. 2506-2513, 2000.
    [Bibtex]
    @article ISI:000087924900003,
    Author = Otyepka, M and Krystof, V and Havlicek, L and Siglerova, V and Strnad, M
       and Koca, J,
    Title = Docking-based development of purine-like inhibitors of cyclin-dependent
       kinase-2,
    Journal = JOURNAL OF MEDICINAL CHEMISTRY,
    Year = 2000,
    Volume = 43,
    Number = 13,
    Pages = 2506-2513,
    Month = JUN 29,
    Abstract = The cell division cycle is controlled by cyclin-dependent kinases (cdk),
       which consist of a catalytic subunit (cdk1-cdk8) and a regulatory
       subunit (cyclin A-H). Purine-like inhibitors of cyclin-dependent kinases
       have recently been found to be of potential use as anticancer drugs.
       Rigid and flexible docking techniques were used for analysis of binding
       mode and design of new inhibitors. X-ray structures of three (ATP,
       olomoucine, roscovitine) cdk2 complexes were available at the beginning
       of the study and were used to optimize the docking parameters. The new
       potential inhibitors were then docked into the cdk2 enzyme, and the
       enzyme/inhibitor interaction energies were calculated and tested against
       the assayed activities of cdk1 (37 compounds) and cdk2 (9 compounds). A
       significant rank correlation between the activity and the rigid docking
       interaction energy has been found. This implies that (i) the rigid
       docking can be used as a tool for qualitative prediction of activity and
       (ii) values obtained by the rigid docking technique into the cdk2 active
       site can also be used for the prediction of cdk1 activity. While the
       resulting geometries obtained by the rigid docking are in good agreement
       with the X-ray data, the flexible docking did not always produce the
       same inhibitor conformation as that found in the crystal.,
    DOI = 10.1021/jm990506w,
    ISSN = 0022-2623,
    Unique-ID = ISI:000087924900003,