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Computational Enzymology

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Biomolecular Simulations

Part of the book series: Methods in Molecular Biology ((MIMB,volume 924))

Abstract

Techniques for modelling enzyme-catalyzed reaction mechanisms are making increasingly important contributions to biochemistry. They can address fundamental questions in enzyme catalysis and have the potential to contribute to practical applications such as drug development.

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References

  1. Lonsdale R, Ranaghan KE, Mulholland AJ (2010) Computational enzymology. Chem Commun 46:2354–2372

    Article  CAS  Google Scholar 

  2. Senn HM, Thiel W (2009) QM/MM methods for biomolecular systems. Angew Chem Int Ed Engl 48:1198–1229

    Article  PubMed  CAS  Google Scholar 

  3. van der Kamp MW, Mulholland AJ (2008) Computational enzymology: insight into biological catalysts from modelling. Nat Prod Rep 25:1001–1014

    Article  PubMed  CAS  Google Scholar 

  4. Mulholland AJ (2005) Modelling enzyme reaction mechanisms, specificity and catalysis. Drug Discov Today 10:1393–1402

    Article  PubMed  CAS  Google Scholar 

  5. Garcia-Viloca M, Gao J, Karplus M, Truhlar DG (2004) How enzymes work: analysis by modern rate theory and computer simulations. Science 303:186–195

    Article  PubMed  CAS  Google Scholar 

  6. Warshel A (2003) Computer simulations of enzyme catalysis: methods, progress, and insights. Annu Rev Biophys Biomol Struct 32:425–443

    Article  PubMed  CAS  Google Scholar 

  7. Friesner RA, Guallar V (2005) Ab initio quantum chemical and mixed quantum mechanics/molecular mechanics (QM/MM) methods for studying enzymatic catalysis. Annu Rev Phys Chem 56:389–427

    Article  PubMed  CAS  Google Scholar 

  8. Martí S, Roca M, Andrés J, Moliner V, Silla E, Tuñón I, Bertrán J (2004) Theoretical insights in enzyme catalysis. Chem Soc Rev 33:98–107

    Article  PubMed  CAS  Google Scholar 

  9. Himo F (2006) Quantum chemical modeling of enzyme active sites and reaction mechanisms. Theor Chem Acc 116:232–240

    Article  CAS  Google Scholar 

  10. Warshel A, Sharma PK, Kato M, Xiang Y, Liu HB, Olsson MHM (2006) Electrostatic basis for enzyme catalysis. Chem Rev 106:3210–3235

    Article  PubMed  CAS  Google Scholar 

  11. Senn HM, Thiel W (2007) QM/MM studies of enzymes. Curr Opin Chem Biol 11:182–187

    Article  PubMed  CAS  Google Scholar 

  12. Mulholland AJ, Grant GH, Richards WG (1993) Computer modelling of enzyme catalysed reaction mechanisms. Protein Eng 6:133–147

    Article  PubMed  CAS  Google Scholar 

  13. Mulholland AJ, Karplus M (1996) Simulations of enzymic reactions. Biochem Soc Trans 24:247–254

    PubMed  CAS  Google Scholar 

  14. Åqvist J, Warshel A (1993) Simulation of enzyme reactions using valence bond force fields and other hybrid quantum/classical approaches. Chem Rev 93:2523–2544

    Article  Google Scholar 

  15. Warshel A, Levitt M (1976) Theoretical studies of enzymic reactions: dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme. J Mol Biol 103:227–249

    Article  PubMed  CAS  Google Scholar 

  16. Scheiner S, Lipscomb WN (1976) Catalytic mechanism of serine proteinases. Proc Natl Acad Sci USA 73:432–436

    Article  PubMed  CAS  Google Scholar 

  17. Claeyssens F, Harvey JN, Manby FR, Mata RA, Mulholland AJ, Ranaghan KE, Schultz M, Thiel S, Thiel W, Werner H-J (2006) High accuracy computation of reaction barriers in enzymes. Angew Chem Int Ed 45:6856–6859

    Article  CAS  Google Scholar 

  18. Mulholland AJ (2007) Chemical accuracy in QM/MM calculations on enzyme-catalysed reactions. Chem Cent J 1:19

    Article  PubMed  CAS  Google Scholar 

  19. Braun-Sand S, Olsson MHM, Warshel A (2005) Computer modeling of enzyme catalysis and its relationship to concepts in physical organic chemistry. Adv Phys Org Chem 40:201–245

    Article  CAS  Google Scholar 

  20. Vocadlo DJ, Davies GJ, Laine R, Withers SG (2001) Catalysis by hen egg white lysozyme proceeds via a covalent intermediate. Nature 412:3835–3838

    Article  Google Scholar 

  21. Bowman AL, Grant IM, Mulholland AJ (2008) QM/MM simulations predict a covalent intermediate in the hen egg white lysozyme reaction with its natural substrate. Chem Commun 7:4425–4427

    Article  CAS  Google Scholar 

  22. Cleland WW, Frey PA, Gerlt JA (1998) The low barrier hydrogen bond in enzymatic catalysis. J Biol Chem 273:25529–25532

    Article  PubMed  CAS  Google Scholar 

  23. Mulholland AJ, Lyne PD, Karplus M (2000) Ab initio QM/MM study of the citrate synthase mechanism: a low-barrier hydrogen bond is not involved. J Am Chem Soc 122:534–535

    Article  CAS  Google Scholar 

  24. Schutz CN, Warshel A (2004) The low barrier hydrogen bond (LBHB) proposal revisited: the case of the Asp · His pair in serine proteases. Proteins 55:711–723

    Article  PubMed  CAS  Google Scholar 

  25. Molina PA, Jensen JH (2003) A predictive model of strong hydrogen bonding in proteins: the Nδ1–H–Oδ1 hydrogen bond in low-pH α-chymotrypsin and α-lytic protease. J Phys Chem B 107:6226–6233

    Article  CAS  Google Scholar 

  26. Hur S, Bruice TC (2003) Just a near attack conformer for catalysis (chorismate to prephenate rearrangements in water, antibody, enzymes, and their mutants). J Am Chem Soc 125:10540–10542

    Article  PubMed  CAS  Google Scholar 

  27. Ranaghan KE, Mulholland AJ (2004) Conformational effects in enzyme catalysis: QM/MM free energy calculation of the ‘NAC’ contribution in chorismate mutase. Chem Commun 10:1238–1239

    Article  CAS  Google Scholar 

  28. Olsson MH, Parson WW, Warshel A (2006) Dynamical contributions to enzyme catalysis: critical tests of a popular hypothesis. Chem Rev 106:1737–1756

    Article  PubMed  CAS  Google Scholar 

  29. Hammes-Schiffer S, Watney JB (2006) Hydride transfer catalyzed by Escherichia coli and Bacillus subtilis dihydrofolate reductase: Coupled motions and distal mutations. Phil Trans Roy Soc B 361:1365–1373

    Article  CAS  Google Scholar 

  30. Masgrau L, Roujeinikova A, Johannissen LO, Hothi P, Basran J, Ranaghan KE, Mulholland AJ, Sutcliffe MJ, Scrutton NS, Leys D (2006) Atomic description of an enzyme reaction dominated by proton tunneling. Science 312:237–241

    Article  PubMed  CAS  Google Scholar 

  31. Hatcher E, Soudackov AV, Hammes-Schiffer S (2007) Proton-coupled electron transfer in soybean lipoxygenase: dynamical behavior and temperature dependence of kinetic isotope effects. J Am Chem Soc 129:187–196

    Article  PubMed  CAS  Google Scholar 

  32. Limbach HH, Lopez JM, Kohen A (2006) Arrhenius curves of hydrogen transfers: tunnel effects, isotope effects and effects of pre-equilibria. Phil Trans Roy Soc B 361:1399–1415

    Article  CAS  Google Scholar 

  33. Nagel ZD, Klinman JP (2006) Tunneling and dynamics in enzymatic hydride transfer. Chem Rev 106:3095–3118

    Article  PubMed  CAS  Google Scholar 

  34. Villa J, Strajbl M, Glennon TM, Sham YY, Chu ZT, Warshel A (2000) How important are entropic contributions to enzyme catalysis? Proc Natl Acad Sci USA 97:11899–11904

    Article  PubMed  CAS  Google Scholar 

  35. Lonsdale R, Harvey JN, Manby FR, Mulholland AJ (2011) Comment on “A stationary-wave model of enzyme catalysis” by Carlo Canepa. J Comput Chem 32:368–369

    Article  PubMed  CAS  Google Scholar 

  36. Ridder L, Harvey JN, Rietjens IMCM, Vervoort J, Mulholland AJ (2003) Ab initio QM/MM modeling of the hydroxylation step in p-hydroxybenzoate hydroxylase. J Phys Chem B 107:2118–2126

    Article  CAS  Google Scholar 

  37. Ridder L, Mulholland AJ, Rietjens IMCM, Vervoort J (2000) A quantum mechanical/molecular mechanical study of the hydroxylation of phenol and halogenated derivatives by phenol hydroxylase. J Am Chem Soc 122:8728–8738

    Article  CAS  Google Scholar 

  38. Bjelic S, Åqvist J (2004) Prediction of structure, substrate binding mode, mechanism, and rate for a malaria protease with a novel type of active site. Biochemistry 43:14521–14528

    Article  PubMed  CAS  Google Scholar 

  39. Zhang YK, Kua J, McCammon JA (2003) Influence of structural fluctuation on enzyme reaction energy barriers in combined quantum mechanical/molecular mechanical studies. J Phys Chem B 107:4459–4463

    Article  CAS  Google Scholar 

  40. Gao JL, Truhlar DG (2002) Quantum mechanical methods for enzyme kinetics. Annu Rev Phys Chem 53:467–505

    Article  PubMed  CAS  Google Scholar 

  41. Karplus M, Gao YQ, Ma JP, van der Vaart A, Yang W (2005) Protein structural transitions and their functional role. Phil Trans R Soc A 363:331–355

    Article  PubMed  CAS  Google Scholar 

  42. Fersht A (1999) Structure and mechanism in protein science. A guide to enzyme catalysis and protein folding. Freeman, New York

    Google Scholar 

  43. Olsson MHM, Warshel A (2004) Solute solvent dynamics and energetics in enzyme catalysis: the S(N)2 reaction of dehalogenase as a general benchmark. J Am Chem Soc 126:15167–15179

    Article  PubMed  CAS  Google Scholar 

  44. Wolf-Watz M, Thai V, Henzler-Wildman K, Hadjipaylou G, Eisenmesser EZ, Kern D (2004) Linkage between dynamics and catalysis in a thermophilic-mesophilic enzyme pair. Nat Struct Mol Biol 11:945–949

    Article  PubMed  CAS  Google Scholar 

  45. Kohen A, Cannio R, Bartolucci S, Klinman JP (1999) Enzyme dynamics and hydrogen tunneling in a thermophilic alcohol dehydrogenase. Nature 399:496–499

    Article  PubMed  CAS  Google Scholar 

  46. Sutcliffe MJ, Masgrau L, Roujeinikova A, Johannissen LO, Hothi P, Basran J, Ranaghan KE, Mulholland AJ, Leys D, Scrutton NS (2006) Hydrogen tunnelling in enzyme-catalysed H-transfer reactions: flavoprotein and quinoprotein systems. Phil Trans Roy Soc B 361:1375–1386

    Article  CAS  Google Scholar 

  47. Ranaghan KE, Mulholland AJ (2010) Computer simulations of quantum tunnelling in enzyme-catalysed hydrogen transfer reactions. Interdiscip Sci 2:78–97

    Article  PubMed  CAS  Google Scholar 

  48. Pentikäinen U, Pentikäinen OT, Mulholland AJ (2008) Cooperative symmetric to asymmetric conformational transition of the apo-form of scavenger decapping enzyme revealed by simulations. Proteins 70:498–508

    Article  PubMed  CAS  Google Scholar 

  49. Lodola A, Mor M, Zurek J, Tarzia G, Piomelli D, Harvey JN, Mulholland AJ (2007) Conformational effects in enzyme catalysis: reaction via a high energy conformation in fatty acid amide hydrolase. Biophys J 92:L20–L22

    Article  PubMed  CAS  Google Scholar 

  50. Case DA, Cheatham TE III, Darden T, Gohlke H, Luo R, Merz KM Jr, Onufriev A, Simmerling C, Wang B, Woods R (2005) The AMBER biomolecular simulation programs. J Comput Chem 26:1668–1688 (see http://amber.scripps.edu/)

    Article  PubMed  CAS  Google Scholar 

  51. Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983) CHARMM: a program for macromolecular energy, minimization, and dynamics calculations. J Comput Chem 4:187–217, (See also http://www.charmm.org)

    Article  CAS  Google Scholar 

  52. Scott WRP, Hunenberger PH, Tironi IG, Mark AE, Billeter SR, Fennen J, Torda AE, Huber T, Kruger P, van Gunsteren WF (1999) The GROMOS biomolecular simulation program package. J Phys Chem A 103:3596–3607, (see http://www.igc.ethz.ch/gromos/gromos.html)

    Article  CAS  Google Scholar 

  53. Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kale L, Schulten K (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26:1781–1802, (see http://www.ks.uiuc.edu/Research/namd/)

    Article  PubMed  CAS  Google Scholar 

  54. Ponder JW, Richards FM (1987) An efficient newton-likemethod for molecular mechanics energy minimization of large molecules. J Comput Chem 8:1016–1024, (see http://dasher.wustl.edu/tinker/)

    Article  CAS  Google Scholar 

  55. Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118:11225–11236

    Article  CAS  Google Scholar 

  56. Kaminski GA, Friesner RA, Tirado-Rives J, Jorgensen WL (2001) Evaluation and reparametrization of the OPLSAA force field for proteins via comparison with accurate quantum chemical calculations on peptides. J Phys Chem B 105:6474–6487

    Article  CAS  Google Scholar 

  57. MacKerell AD Jr, Bashford D, Bellott M, Dunbrack RL Jr, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph-McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher WE III, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiórkiewicz-Kuczera J, Yin D, Karplus M (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102:3586–3616

    Article  CAS  Google Scholar 

  58. Cornell WD, Cieplak P, Bayly CI, Gould IR, Merz KM, Ferguson DM, Spellmeyer DC, Fox T, Caldwell JW, Kollman PA (1995) A 2nd generation force-field for the simulation of proteins, nucleic-acids, and organic molecules. J Am Chem Soc 117:5179–5197

    Article  CAS  Google Scholar 

  59. Mackerell AD (2005) Empirical force fields for proteins: current status and future directions. Ann Rep Comp Chem 1:91–111

    Article  CAS  Google Scholar 

  60. Ponder JW, Case DA (2003) Force fields for protein simulations. Adv Protein Chem 66:27–75

    Article  PubMed  CAS  Google Scholar 

  61. Cheatham TE III (2005) Molecular modeling and atomistic simulation of nucleic acids. Ann Rep Comp Chem 1:75–90

    Article  CAS  Google Scholar 

  62. Cheatham TE III (2004) Simulation and modeling of nucleic acid structure, dynamics and interactions. Curr Opin Struct Biol 14:360–367

    Article  PubMed  CAS  Google Scholar 

  63. Foloppe N, MacKerell AD (2000) All-atom empirical force field for nucleic acids: I parameter optimization based on small molecule and condensed phase macromolecular target data. J Comput Chem 21:86–104

    Article  CAS  Google Scholar 

  64. MacKerell AD, Banavali NK (2000) All-atom empirical force field for nucleic acids: II application to molecular dynamics simulations of DNA and RNA in solution. J Comput Chem 21:105–120

    Article  CAS  Google Scholar 

  65. Cheatham TE, Cieplak P, Kollman PA (1999) A modified version of the Cornell et al. force field with improved sugar pucker phases and helical repeat. J Biomol Struct Dyn 16:845–862

    Article  PubMed  CAS  Google Scholar 

  66. Feller SE, Yin DX, Pastor RW, MacKerell AD (1997) Molecular dynamics simulation of unsaturated lipid bilayers at low hydration: parameterization and comparison with diffraction studies. Biophys J 73:2269–2279

    Article  PubMed  CAS  Google Scholar 

  67. Jorgensen WL, Tirado-Rives J (2005) Potential energy functions for atomic-level simulations of water and organic and biomolecular systems. Proc Natl Acad Sci USA 102:6665–6670

    Article  PubMed  CAS  Google Scholar 

  68. Kim BC, Young T, Harder E, Friesner RA, Berne BJ (2005) Structure and dynamics of the solvation of bovine pancreatic trypsin inhibitor in explicit water: a comparative study of the effects of solvent and protein polarizability. J Phys Chem B 109:16529–16538

    Article  PubMed  CAS  Google Scholar 

  69. Shaw KE, Woods CJ, Mulholland AJ (2010) Compatibility of quantum chemical methods and empirical (MM) water models in quantum mechanics/molecular mechanics liquid water simulations. J Phys Chem Lett 1:219–223

    Article  CAS  Google Scholar 

  70. Lim D, Jenson J, Repasky MP, Jorgensen WL (1999) Solvent as catalyst: computational studies of organic reactions in solution. In: Truhlar DG, Morokuma K (eds) Transition state modeling for catalysis. American Chemical Society, Washington DC

    Google Scholar 

  71. Bentzien J, Muller RP, Florian J, Warshel A (1998) Hybrid ab initio quantum mechanics molecular mechanics calculations of free energy surfaces for enzymatic reactions: the nucleophilic attack in subtilisin. J Phys Chem B 102:2293–2301

    Article  CAS  Google Scholar 

  72. Warshel A (1997) Computer modeling of chemical reactions in enzymes and solutions. John Wiley & Sons, New York

    Google Scholar 

  73. Villa J, Warshel A (2001) Energetics and dynamics of enzymatic reactions. J Phys Chem B 105:7887–7907

    Article  CAS  Google Scholar 

  74. Warshel A, Sharma PK, Chu ZT, Åqvist J (2007) Electrostatic contributions to binding of transition state analogues can be different from the corresponding contributions to catalysis: phenolates binding to the oxyanion hole of ketosteroid isomerase. Biochemistry 46:1466–1476

    Article  PubMed  CAS  Google Scholar 

  75. Bjelic S, Åqvist J (2006) Catalysis and linear free energy relationships in aspartic proteases. Biochemistry 45:7709–7723

    Article  PubMed  CAS  Google Scholar 

  76. Trobro S, Åqvist J (2005) Mechanism of peptide bond synthesis on the ribosome. Proc Natl Acad Sci USA 102:12395–12400

    Article  PubMed  CAS  Google Scholar 

  77. Sharma PK, Xiang Y, Katom M, Warshel A (2005) What are the roles of substrate-assisted catalysis and proximity effects in peptide bond formation by the ribosome? Biochemistry 44:11307–11314

    Article  PubMed  CAS  Google Scholar 

  78. Hammes-Schiffer S (2004) Quantum-classical simulation methods for hydrogen transfer in enzymes: a case study of dihydrofolate reductase. Curr Opin Struct Biol 14:192–201

    Article  PubMed  CAS  Google Scholar 

  79. Liu HB, Warshel A (2007) Origin of the temperature dependence of isotope effects in enzymatic reactions: the case of dihydrofolate reductase. J Phys Chem B 111:7852–7861

    Article  PubMed  CAS  Google Scholar 

  80. Sharma PK, Chu ZT, Olsson MHM, Warshel A (2007) A new paradigm for electrostatic catalysis of radical reactions in vitamin B12 enzymes. Proc Natl Acad Sci USA 2007(104):9661–9666

    Article  CAS  Google Scholar 

  81. Van derVaart A, Gogonea V, Dixon SL, Merz KM (2000) Linear scaling molecular orbital calculations of biological systems using the semiempirical divide and conquer method. J Comput Chem 21:1494–1504

    Article  Google Scholar 

  82. Khandogin J, York DM (2004) Quantum descriptors for biological macromolecules from linear-scaling electronic structure methods. Proteins 56:724–737

    Article  PubMed  CAS  Google Scholar 

  83. Khandogin J, Musier-Forsyth K, York DM (2003) Insights into the regioselectivity and RNA-binding affinity of HIV-1 nucleocapsid protein from linear-scaling quantum methods. J Mol Biol 330:993–1004

    Article  PubMed  CAS  Google Scholar 

  84. Lonsdale R, Harvey JN, Mulholland AJ (2010) Inclusion of dispersion effects significantly improves accuracy of calculated reaction barriers for cytochrome p450 catalyzed reactions. J Phys Chem Lett 1:3232–3237

    Article  CAS  Google Scholar 

  85. Himo F, Siegbahn PE (2003) Quantum chemical studies of radical-containing enzymes. Chem Rev 103:2421–2456

    Article  PubMed  CAS  Google Scholar 

  86. Siegbahn PE, Himo F (2009) Recent developments of the quantum chemical cluster approach for modeling enzyme reactions. J Biol Inorg Chem 14:643–651

    Article  PubMed  CAS  Google Scholar 

  87. Woodcock HL, Hodoscek M, Sherwood P, Lee YS, Schaefer HF, Brooks BR (2003) Exploring the quantum mechanical/molecular mechanical replica path method: a pathway optimization of the chorismate to prephenate Claisen rearrangement catalyzed by chorismate mutase. Theor Chem Acc 109:140–148

    Article  CAS  Google Scholar 

  88. Field MJ, Bash PA, Karplus M (1990) A combined quantum-mechanical and molecular mechanical potential for molecular-dynamics simulations. J Comput Chem 11:700–733

    Article  CAS  Google Scholar 

  89. Lyne PD, Hodoscek M, Karplus M (1999) A hybrid QM–MM potential employing Hartree–Fock or density functional methods in the quantum region. J Phys Chem A 103:3462–3471

    Article  CAS  Google Scholar 

  90. Cui Q, Elstner M, Kaxiras E, Frauenheim T, Karplus M (2001) A QM/MM implementation of the self-consistent charge density functional tight binding (SCC-DFTB) method. J Phys Chem B 105:569–585

    Article  CAS  Google Scholar 

  91. Marti S, Moliner V (2005) Improving the QM/MM description of chemical processes: a dual level strategy to explore the potential energy surface in very large systems. J Chem Theory Comput 1:1008–1016

    Article  CAS  Google Scholar 

  92. Prat-Resina X, Bofill JM, Gonzalez-Lafont A, Lluch JM (2004) Geometry optimization and transition state search in enzymes: different options in the microiterative method. Int J Quantum Chem 98:367–377

    Article  CAS  Google Scholar 

  93. Ridder L, Rietjens IMCM, Vervoort J, Mulholland AJ (2002) Quantum mechanical/molecular mechanical free energy simulations of the glutathione S-transferase (M1-1) reaction with phenanthrene 9,10-oxide. J Am Chem Soc 124:9926–9936

    Article  PubMed  CAS  Google Scholar 

  94. Ranaghan KE, Ridder L, Szefczyk B, Sokalski WA, Hermann JC, Mulholland AJ (2004) Transition state stabilization and substrate strain in enzyme catalysis: ab initio QM/MM modelling of the chorismate mutase reaction. Org Biomol Chem 2:968–980

    Article  PubMed  CAS  Google Scholar 

  95. Lodola A, Mor M, Hermann JC, Tarzia G, Piomelli D, Mulholland AJ (2005) QM/MM modelling of oleamide hydrolysis in fatty acid amide hydrolase (FAAH) reveals a new mechanism of nucleophile activation. Chem Commun 35:4399–4401

    Article  CAS  Google Scholar 

  96. Riccardi D, Schaefer P, Cui Q (2005) pK a calculations in solution and proteins with QM/MM free energy perturbation simulations: a quantitative test of QM/MM protocols. J Phys Chem B 109:17715–17733

    Article  PubMed  CAS  Google Scholar 

  97. Raha K, Merz KM (2004) A quantum mechanics-based scoring function: study of zinc ion-mediated ligand binding. J Am Chem Soc 126:1020–1021

    Article  PubMed  CAS  Google Scholar 

  98. Bakowies D, Thiel W (1996) Hybrid models for combined quantum mechanical and molecular mechanical approaches. J Phys Chem 100:10580–10594

    Article  CAS  Google Scholar 

  99. Svensson M, Humbel S, Froese RDJ, Matsubara T, Sieber S, Morokuma K (1996) ONIOM: A multilayered Integrated MO + MM Method for geometry optimizations and single point energy predictions. A test for Diels − Alder reactions and Pt(P(t-Bu)3)2 + H2 oxidative addition. J Phys Chem 100:19357–19363

    Article  CAS  Google Scholar 

  100. Antes I, Thiel W (1999) Adjusted connection atoms for combined quantum mechanical and molecular mechanical methods. J Phys Chem A 103:9290–9295

    Article  CAS  Google Scholar 

  101. Jensen L, van Duijnen PT (2005) The first hyperpolarizability of p-nitroaniline in 1,4-dioxane: a quantum mechanical/molecular mechanics study. J Chem Phys 123:Art. No. 074307

    Google Scholar 

  102. Cui Q, Karplus M (2002) Quantum mechanics/molecular mechanics studies of triosephosphate isomerase-catalyzed reactions: effect of geometry and tunneling on proton-transfer rate constants. J Am Chem Soc 124:3093–3124

    Article  PubMed  CAS  Google Scholar 

  103. Riccardi D, Li GH, Cui Q (2004) Importance of van der Waals interactions in QM/MM simulations. J Phys Chem B 108:6467–6478

    Article  PubMed  CAS  Google Scholar 

  104. Poulsen TD, Garcia-Viloca M, Gao JL, Truhlar DG (2003) Free energy surface, reaction paths, and kinetic isotope effect of short-chain acyl-coa dehydrogenase. J Phys Chem B 107:9567–9578

    Article  CAS  Google Scholar 

  105. Brooks CL III, Karplus M, Pettitt BM (1988) Proteins, a theoretical perspective of dynamics, structure and thermodynamics. Wiley, New York

    Google Scholar 

  106. Nam K, Gao JL, York DM (2005) An efficient linear-scaling ewald method for long-range electrostatic interactions in combined QM/MM calculations. J Chem Theory Comput 1:2–13

    Article  CAS  Google Scholar 

  107. Schaefer P, Riccardi D, Cui Q (2005) Reliable treatment of electrostatics in combined QM/MM simulation of macromolecules. J Chem Phys 123:Art. No. 014905

    Article  CAS  Google Scholar 

  108. Im W, Berneche S, Roux B (2001) Generalized solvent boundary potentials for computer simulations. J Chem Phys 114:2924–2937

    Article  CAS  Google Scholar 

  109. Monard G, Loos M, Théry V, Baka K, Rivail J-L (1996) Hybrid classical quantum force field for modelling very large molecules. Int J Quantum Chem 58:153–159

    Article  CAS  Google Scholar 

  110. Assfeld X, Rivail J-L (1996) Quantum chemical computations on parts of large molecules: The ab initio local self consistent field method. Chem Phys Lett 263:100–106

    Article  CAS  Google Scholar 

  111. Gao J, Amara P, Alhambra C, Field MJ (1998) Method for the treatment of boundary atoms in combined QM/MM calculations. J Phys Chem A 102:4714–4721

    Article  CAS  Google Scholar 

  112. Ferre N, Assfeld X, Rivail J-L (2002) Specific force field parameters determination for the hybrid ab initio QM/MM LSCF method. J Comput Chem 23:610–624

    Article  PubMed  CAS  Google Scholar 

  113. Antonczak S, Monard G, Ruiz-Lopez MF, Rivail J-L (1998) Modeling of Peptide Hydrolysis by Thermolysin. A Semiempirical and QM/MM Study. J Am Chem Soc 120:8825–8833

    Article  CAS  Google Scholar 

  114. Garcia-Viloca M, Gao JL (2004) Generalized hybrid orbital for the treatment of boundary atoms in combined quantum mechanical and molecular mechanical calculations using the semiempirical parameterized model 3 method. Theor Chem Acc 111:280–286

    Article  CAS  Google Scholar 

  115. Wesolowski TA, Warshel A (1993) Frozen density functional approach for ab-initio calculations of solvated molecules. J Phys Chem 97:8050–8053

    Article  CAS  Google Scholar 

  116. Pu JZ, Gao JL, Truhlar DG (2004) Generalized hybrid orbital (GHO) method for combining ab initio hartree—fock wave functions with molecular mechanics. J Phys Chem A 108:632–650

    Article  CAS  Google Scholar 

  117. Pu JZ, Gao JL, Truhlar DG (2004) Combining self-consistent-charge density-functional tight-binding (SCC-DFTB) with molecular mechanics by the generalized hybrid orbital (GHO) Method. J Phys Chem A 108:5454–5463

    Article  CAS  Google Scholar 

  118. Pu JZ, Gao JL, Truhlar DG (2005) Generalized hybrid-orbital method for combining density functional theory with molecular mechanicals. Chemphyschem 6:1853–1865

    Article  PubMed  CAS  Google Scholar 

  119. Amara P, Field MJ (2003) Evaluation of an ab-initio quantum mechanical molecular mechanical hybrid-potential link-atom method. Theor Chem Acc 109:43–52

    Article  CAS  Google Scholar 

  120. HyperChem Users Manual (2002) HyperCube, Inc: Waterloo, Ontario, Canada

    Google Scholar 

  121. Reuter N, Dejaegere A, Maigret B, Karplus M (2000) Frontier bonds in QM/MM methods: a comparison of different approaches. J Phys Chem A 104:1720–1735

    Article  CAS  Google Scholar 

  122. Zhang Y, Lee T-S, Yang W (1999) A pseudobond approach to combining quantum mechanical and molecular mechanical methods. J Chem Phys 110:46–54

    Article  CAS  Google Scholar 

  123. Monard G, Prat-Resina X, Gonzalez-Lafont A, Lluch JM (2003) Determination of enzymatic reaction pathways using QM/MM methods. Int J Quant Chem 93:229–244

    Article  CAS  Google Scholar 

  124. Das D, Eurenius KP, Billings EM, Sherwood P, Chatfield DC, Hodoscek M, Brooks BR (2002) Optimization of quantum mechanical molecular mechanical partitioning schemes: Gaussian delocalization of molecular mechanical charges and the double link atom method. J Chem Phys 117:10534–10547

    Article  CAS  Google Scholar 

  125. Konig PH, Hoffmann M, Frauenheim T, Cui Q (2005) A critical evaluation of different QM/MM frontier treatments with SCC-DFTB as the QM method. J Phys Chem B 109:9082–9095

    Article  PubMed  CAS  Google Scholar 

  126. Klahn M, Braun-Sand S, Rosta E, Warshel A (2005) On possible pitfalls in ab initio quantum mechanics/molecular mechanics minimization approaches for studies of enzymatic reactions. J Phys Chem B 109:15645–15650

    Article  PubMed  CAS  Google Scholar 

  127. Lodola A, Sirirak J, Fey N, Rivara S, Mor M, Mulholland AJ (2010) Structural fluctuations in enzyme-catalyzed reactions: determinants of reactivity in fatty acid amide hydrolase from multivariate statistical analysis of quantum mechanics/molecular mechanics paths. J Chem Theor Comput 6:2948–2960

    Article  CAS  Google Scholar 

  128. Bowman AL, Ridder L, Rietjens IMCM, Vervoort J, Mulholland AJ (2007) Molecular determinants of xenobiotic metabolism: QM/MM simulation of the conversion of 1-chloro-2,4-dinitrobenzene catalyzed by M1-1 glutathione S-transferase. Biochemistry 46:6353–6363

    Article  PubMed  CAS  Google Scholar 

  129. Acevedo O, Jorgensen WL (2010) Advances in quantum and molecular mechanical (QM/MM) simulations for organic and enzymatic reactions. Acc Chem Res 43:142–151

    Article  PubMed  CAS  Google Scholar 

  130. Woods CJ, Manby FR, Mulholland AJ (2008) An efficient method for the calculation of quantum mechanics/molecular mechanics free energies. J Chem Phys 128:Art. No. 014109

    Article  CAS  Google Scholar 

  131. Ridder L, Mulholland AJ (2003) Modeling biotransformation reactions by combined quantum mechanical/molecular mechanical approaches: from structure to activity. Curr Top Med Chem 3:1241–1256

    Article  PubMed  CAS  Google Scholar 

  132. van der Kamp MW, Zurek J, Manby FR, Harvey JN, Mulholland AJ (2010) Testing high-level QM/MM methods for modeling enzyme reactions: acetyl-CoA deprotonation in citrate synthase. J Phys Chem B 114:11303–11314

    Article  PubMed  CAS  Google Scholar 

  133. Ranaghan KE, Masgrau L, Scrutton NS, Sutcliffe MJ, Mulholland AJ (2007) Analysis of classical and quantum paths for deprotonation of methylamine by methylamine dehydrogenase. Chemphyschem 8:1816–1835

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

AJM is an EPSRC Leadership Fellow.

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Authors and Affiliations

  1. Dipartimento Farmaceutico, Universitàdegli Studi di Parma, Parma, Italy

    Alessio Lodola

  2. Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol, UK

    Adrian J. Mulholland

Authors
  1. Alessio Lodola
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  2. Adrian J. Mulholland
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Correspondence to Adrian J. Mulholland .

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Editors and Affiliations

  1. DSIMB, UMR-S 665, INSERM, rue Alexandre Cabanel 6, Paris, 75015, France

    Luca Monticelli

  2. , Department of Applied Physics, Aalto University, Otakaari, AALTO, FI-00076, Finland

    Emppu Salonen

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Lodola, A., Mulholland, A.J. (2013). Computational Enzymology. In: Monticelli, L., Salonen, E. (eds) Biomolecular Simulations. Methods in Molecular Biology, vol 924. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-017-5_4

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  • DOI: https://doi.org/10.1007/978-1-62703-017-5_4

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-016-8

  • Online ISBN: 978-1-62703-017-5

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