A Multiscale Approach to Modelling Drug Metabolism by Membrane-Bound Cytochrome P450 Enzymes

PLoS Computational Biology

Volumn 10, Issue 7, 2014, Pages

  Lonsdale, Richard ^a   Rouse, Sarah L ^b   Sansom, Mark S P ^b   Mulholland, Adrian J ^a  

^a UNIVERSITY OF BRISTOL   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

COARSE-GRAINED MODELING; MEMBRANES; METABOLISM; MOLECULAR DYNAMICS; PHYSIOLOGY; QUANTUM THEORY; REACTION KINETICS; SOLUTIONS;

ACTIVE SITE; CYTOCHROME P450 ENZYMES; DRUG METABOLISMS; LIFE-FORMS; MEMBRANE-BOUND; MEMBRANE-BOUND ENZYMES; MEMBRANE-BOUND PROTEINS; MODEL DRUGS; MULTI-SCALE APPROACHES; TRANSMEMBRANE HELIX;

ENZYMES;

CYTOCHROME P450; CYTOCHROME P450 3A4; HEME; WARFARIN; CYP3A4 PROTEIN, HUMAN; CYTOCHROME P450 3A; PROTEIN BINDING;

ARTICLE; DRUG ABSORPTION; DRUG METABOLISM; DRUG STRUCTURE; ENZYME ACTIVE SITE; ENZYME SUBSTRATE; MATHEMATICAL MODEL; MOLECULAR DYNAMICS; MOLECULAR MECHANICS; PROTEIN CONFORMATION; PROTEIN INTERACTION; QUANTUM MECHANICS; BIOLOGY; CELL MEMBRANE; CHEMISTRY; HUMAN; METABOLISM; PLIABILITY; PROCEDURES;

CATALYTIC DOMAIN; CELL MEMBRANE; COMPUTATIONAL BIOLOGY; CYTOCHROME P-450 CYP3A; HEME; HUMANS; MOLECULAR DYNAMICS SIMULATION; PLIABILITY; PROTEIN BINDING; PROTEIN CONFORMATION; WARFARIN;

EID: 84905455465     PISSN: 1553734X     EISSN: 15537358     Source Type: Journal    
DOI: 10.1371/journal.pcbi.1003714     Document Type: Article

References (85)

1. Stansfeld PJ, Sansom MSP, (2011) Molecular simulation approaches to membrane proteins. Structure 19: 1562-72.
2. Stansfeld PJ, Sansom MSP, (2011) From coarse grained to atomistic: A serial multiscale approach to membrane protein simulations. J Chem Theory Comput 7: 1157-1166.
3. van der Kamp MW, Mulholland AJ, (2013) Combined quantum mechanics/molecular mechanics (QM/MM) methods in computational enzymology. Biochemistry 52: 2708-2728.
4. Ortiz de Montellano PR, editor (2005) Cytochrome P450: Structure, Mechanism, and Biochemistry. 3rd edition. New York: Kluwer Academic/Plenum.
5. Black SD, (1992) Membrane topology of the mammalian P450 cytochromes. FASEB J 6: 680-5.
6. Sakaguchi M, Mihara K, Sato R, (1987) A short amino-terminal segment of microsomal cytochrome P-450 functions both as an insertion signal and as a stop-transfer sequence. EMBO J 6: 2425-31.
7. Yuki H, Honma T, Hata M, Hoshino T (2012) Prediction of sites of metabolism in a substrate molecule, instanced by carbamazepine oxidation by {CYP3A4}. Bioorg Med Chem 20: 775 - 783.
8. Lonsdale R, Houghton KT, Zurek J, Bathelt CM, Foloppe N, et al. (2013) Quantum mechanics/molecular mechanics modeling of regioselectivity of drug metabolism in cytochrome P450 2C9. J Am Chem Soc 135: 8001-8015.
9. Oláh J, Mulholland AJ, Harvey JN, (2011) Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450. Proc Natl Acad Sci U S A 108: 6050-5.
10. Williams PA, Cosme J, Ward A, Angove HC, Matak Vinković D, et al. (2003) Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature 424: 464-8.
11. Schoch GA, Yano JK, Wester MR, Griffin KJ, Stout CD, et al. (2004) Structure of human microsomal cytochrome P450 2C8: Evidence for a peripheral fatty acid binding site. J Biol Chem 279: 9497-9503.
12. Yano JK, Wester MR, Schoch GA, Griffin KJ, Stout CD, et al. (2004) The structure of human microsomal cytochrome P450 3A4 determined by X-ray crystallography to 2.05 Å resolution. J Biol Chem 279: 38091-4.
13. Schleinkofer K, Sudarko, Winn PJ, Lüdemann SK, Wade RC, (2005) Do mammalian cytochrome P450s show multiple ligand access pathways and ligand channelling? EMBO Rep 6: 584-9.
14. Denisov IG, Shih AY, Sligar SG, (2012) Structural differences between soluble and membrane bound cytochrome P450s. J Inorg Biochem 108: 150-8.
15. Lomize MA, Lomize AL, Pogozheva ID, Mosberg HI, (2006) OPM: Orientations of Proteins in Membranes database. Bioinformatics 22: 623-625.
16. Baylon JL, Lenov IL, Sligar SG, Tajkhorshid E, (2013) Characterizing the membrane-bound state of cytochrome P450 3A4: Structure, depth of insertion and orientation. J Am Chem Soc 135: 8542-8551.
17. Ohta Y, Kawato S, Tagashira H, Takemori S, Kominami S, (1992) Dynamic structures of adrenocortical cytochrome P-450 in proteoliposomes and microsomes: protein rotation study. Biochemistry 31: 12680-12687.
18. Bond PJ, Holyoake J, Ivetac A, Khalid S, Sansom MSP, (2007) Coarse-grained molecular dynamics simulations of membrane proteins and peptides. J Struct Biol 157: 593-605.
19. Cojocaru V, Balali-Mood K, Sansom MSP, Wade RC, (2011) Structure and dynamics of the membrane-bound cytochrome P450 2C9. PLoS Comput Biol 7: e1002152.
20. Rittle J, Green MT, (2010) Cytochrome P450 Compound I: Capture, characterization, and C-H bond activation kinetics. Science 330: 933-937.
21. Lonsdale R, Harvey JN, Mulholland AJ, (2010) Compound I reactivity defines alkene oxidation selectivity in cytochrome P450cam. J Phys Chem B 114: 1156-62.
22. Lonsdale R, Ranaghan KE, Mulholland AJ, (2010) Computational enzymology. Chem Commun 46: 2354-2372.
23. Lonsdale R, Hoyle S, Grey DT, Ridder L, Mulholland AJ, (2012) Determinants of reactivity and selectivity in soluble epoxide hydrolase from quantum mechanics/molecular mechanics modeling. Biochemistry 51: 1774-1786.
24. Shaik S, Cohen S, Wang Y, Chen H, Kumar D, et al. (2010) P450 enzymes: their structure, reactivity, and selectivity-modeled by QM/MM calculations. Chem Rev 110: 949-1017.
25. Bathelt CM, Zurek J, Mulholland AJ, Harvey JN, (2005) Electronic structure of Compound I in human isoforms of cytochrome P450 from QM/MM modeling. J Am Chem Soc 127: 12900-8.
26. Zurek J, Foloppe N, Harvey JN, Mulholland AJ, (2006) Mechanisms of reaction in cytochrome p450: hydroxylation of camphor in p450cam. Org Biomol Chem 4: 3931-3937.
27. Lonsdale R, Oláh J, Mulholland AJ, Harvey JN, (2011) Does compound I vary significantly between isoforms of cytochrome P450? J Am Chem Soc 133: 15464-74.
28. Lonsdale R, Harvey JN, Mulholland AJ, (2012) A practical guide to modelling enzyme-catalysed reactions. Chem Soc Rev 41: 3025-38.
29. Lonsdale R, Harvey JN, Mulholland AJ, (2012) Effects of dispersion in density functional based quantum mechanical/molecular mechanical calculations on cytochrome P450 catalyzed reactions. J Chem Theory Comput 8: 4637-4645.
30. 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.
31. Shaik S, Kumar D, de Visser SP, Altun A, Thiel W, (2005) Theoretical perspective on the structure and mechanism of cytochrome P450 enzymes. Chem Rev 105: 2279-328.
32. Wade RC, Winn PJ, Schlichting I, Sudarko (2004) A survey of active site access channels in cytochromes P450. J Inorg Biochem 98: 1175-82.
33. Integrating bioinformatics and chemoinformatics approaches for the development of expert systems allowing the in silico prediction of toxicities (etox). Accessed: 1 December 2013. URL http://www.etoxproject.eu/.
34. Kaminsky LS, Zhang ZY, (1997) Human P450 metabolism of warfarin. Pharmacol Ther 73: 67-74.
35. Fishelovitch D, Shaik S, Wolfson HJ, Nussinov R, (2010) How does the reductase help to regulate the catalytic cycle of cytochrome P450 3A4 using the conserved water channel? J Phys Chem B 114: 5964-5970.
36. Gora A, Brezovsky J, Damborsky J, (2013) Gates of enzymes. Chem Rev 113: 5871-5923.
37. Fishelovitch D, Shaik S, Wolfson HJ, Nussinov R, (2009) Theoretical characterization of substrate access/exit channels in the human cytochrome P450 3A4 enzyme: involvement of phenylalanine residues in the gating mechanism. J Phys Chem B 113: 13018-25.
38. Chovancova E, Pavelka A, Benes P, Strnad O, Brezovsky J, et al. (2012) Caver 3.0: A tool for the analysis of transport pathways in dynamic protein structures. PLoS Comput Biol 8: e1002708.
39. Shahrokh K, Cheatham TE 3rd, Yost GS, (2012) Conformational dynamics of CYP3A4 demonstrate the important role of Arg212 coupled with the opening of ingress, egress and solvent channels to dehydrogenation of 4-hydroxy-tamoxifen. Biochim Biophys Acta 1820: 1605-17.
40. Williams PA, Cosme J, Vinković DM, Ward A, Angove HC, et al. (2004) Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science 305: 683-686.
41. Guallar V, Wallrapp F, (2008) Mapping protein electron transfer pathways with QM/MM methods. J R Soc Interface 5: 233-239.
42. Krest CM, Onderko EL, Yosca TH, Calixto JC, Karp RF, et al. (2013) Reactive intermediates in cytochrome P450 catalysis. J Biol Chem 288: 17074-17081.
43. Groves JT, McClusky GA, (1976) Aliphatic hydroxylation via oxygen rebound. Oxygen transfer catalyzed by iron. J Am Chem Soc 98: 859-861.
44. Antony J, Grodzicki M, Trautwein AX, (1997) Local density functional study of oxoiron(IV) porphyrin complexes and their one-electron oxidized derivatives. axial ligand effects. J Phys Chem A 101: 2692-2701.
45. Filatov M, Harris N, Shaik S, (1999) A theoretical study of electronic factors affecting hydroxylation by model ferryl complexes of cytochrome P-450 and horseradish peroxidase. J Chem Soc, Perkin Trans 2 0: 399-410.
46. Loew GH, Harris DL, (2000) Role of the heme active site and protein environment in structure, spectra, and function of the cytochrome p450s. Chem Rev 100: 407-420.
47. Shaik S, de Visser SP, Ogliaro F, Schwarz H, Schröder D (2002) Two-state reactivity mechanisms of hydroxylation and epoxidation by cytochrome P450 revealed by theory. Curr Opin Chem Biol 6: 556 - 567.
48. Sevrioukova IF, Poulos TL, (2012) Structural and mechanistic insights into the interaction of cytochrome P450 3A4 with bromoergocryptine, a type I ligand. J Biol Chem 287: 3510-3517.
49. Sun H, Scott DO, (2011) Metabolism of 4-aminopiperidine drugs by cytochrome P450s: Molecular and quantum mechanical insights into drug design. ACS Med Chem Lett 2: 638-643.
50. Woods CJ, Mulholland AJ (2008) Multiscale modelling of biological systems. In: Chemical Modelling: Applications and Theory, Royal Society of Chemistry volume 5. p13-50.
51. Korzekwa KR, Krishnamachary N, Shou M, Ogai A, Parise RA, et al. (1998) Evaluation of atypical cytochrome P450 kinetics with two-substrate models: evidence that multiple substrates can simultaneously bind to cytochrome p450 active sites. Biochemistry 37: 4137-4147.
52. Schrag ML, Wienkers LC (2001) Covalent alteration of the CYP3A4 active site: Evidence for multiple substrate binding domains. Arch Biochem Biophys 391: 49 - 55.
53. Kapelyukh Y, Paine MJI, Maréchal JD, Sutcliffe MJ, Wolf CR, et al. (2008) Multiple substrate binding by cytochrome P450 3A4: Estimation of the number of bound substrate molecules. Drug Metab Dispos 36: 2136-2144.
54. Fishelovitch D, Hazan C, Hirao H, Wolfson HJ, Nussinov R, et al. (2007) QM/MM study of the active species of the human cytochrome P450 3A4, and the inuence thereof of the multiple substrate binding. J Phys Chem B 111: 13822-13832.
55. Bren U, Oostenbrink C, (2012) Cytochrome P450 3A4 inhibition by ketoconazole: Tackling the problem of ligand cooperativity using molecular dynamics simulations and free-energy calculations. J Chem Inf Model 52: 1573-1582.
56. Limongelli V, Bonomi M, Parrinello M, (2013) Funnel metadynamics as accurate binding free-energy method. Proc Natl Acad Sci U S A 110: 6358-6363.
57. Warshel A, (2003) Computer simulations of enzyme catalysis: Methods, progress, and insights. Annu Rev Biophys Biomol Struct 32: 425-443.
58. Eswar N, Webb B, Marti-Renom MA, Madhusudhan MS, Eramian D, et al. (2006) Comparative protein structure modeling using Modeller. Curr Protoc Bioinformatics Chapter 5: Unit 5.6.
59. Trott O, Olson AJ, (2010) AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, effcient optimization, and multithreading. J Comput Chem 31: 455-461.
60. Marrink SJ, de Vries AH, Mark AE, (2004) Coarse grained model for semiquantitative lipid simulations. J Phys Chem B 108: 750-760.
61. Periole X, Marrink SJ, (2013) The Martini coarse-grained force field. Methods Mol Biol 924: 533-65.
62. Monticelli L, Kandasamy SK, Periole X, Larson RG, Tieleman DP, et al. (2008) The MARTINI coarse-grained force field: Extension to proteins. J Chem Theory Comput 4: 819-834.
63. Marrink SJ, Risselada HJ, Yefimov S, Tieleman DP, de Vries AH, (2007) The MARTINI force field: coarse grained model for biomolecular simulations. J Phys Chem B 111: 7812-24.
64. Berendsen H, van der Spoel D, van Drunen R (1995) GROMACS: A message-passing parallel molecular dynamics implementation. Comp Phys Commun 91: 43 - 56.
65. Hess B, Kutzner C, van der Spoel D, Lindahl E, (2008) GROMACS 4: Algorithms for highly effcient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4: 435-447.
66. Lindahl E, Hess B, van der Spoel D, (2001) GROMACS 3.0: a package for molecular simulation and trajectory analysis. J Mol Model 7: 306-317.
67. Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, et al. (2005) GROMACS: Fast, exible, and free. J Comput Chem 26: 1701-1718.
68. Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, et al. (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26: 1781-1802.
69. Mackerell AD, Feig M, Brooks CL, (2004) Extending the treatment of backbone energetics in protein force fields: Limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. J Comput Chem 25: 1400-1415.
70. MacKerell AD, Bashford D, Bellott, Dunbrack RL, Evanseck JD, et al. (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102: 3586-3616.
71. Klauda JB, Venable RM, Freites JA, O'Connor JW, Tobias DJ, et al. (2010) Update of the CHARMM all-atom additive force field for lipids: Validation on six lipid types. J Phys Chem B 114: 7830-7843.
72. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML, (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79: 926-935.
73. Martyna GJ, Tobias DJ, Klein ML, (1994) Constant pressure molecular dynamics algorithms. J Chem Phys 101: 4177-4189.
74. Feller SE, Zhang Y, Pastor RW, Brooks BR, (1995) Constant pressure molecular dynamics simulation: The langevin piston method. J Chem Phys 103: 4613-4621.
75. Humphrey W, Dalke A, Schulten K, (1996) VMD - Visual Molecular Dynamics. J Mol Graph 14: 33-38.
76. Grossfield A, Zuckerman DM (2009) Chapter 2 quantifying uncertainty and sampling quality in biomolecular simulations. Annu Rep Comput Chem 5: 23 - 48.
77. Harvey JN, (2004) Spin-forbidden CO ligand recombination in myoglobin. Faraday Discuss 127: 165-177.
78. Bochevarov AD, Harder E, Hughes TF, Greenwood JR, Braden DA, et al. (2013) Jaguar: A highperformance quantum chemistry software program with strengths in life and materials sciences. Int J Quantum Chem 113: 2110-2142.
79. Singh UC, Kollman PA, (1986) A combined ab initio quantum mechanical and molecular mechanical method for carrying out simulations on complex molecular systems: Applications to the CH3Cl + Cl exchange reaction and gas phase protonation of polyethers. J Comput Chem 7: 718-730.
80. Vosko SH, Wilk L, Nusair M, (1980) Accurate spin-dependent electron liquid correlation energies for local spin density calculations: a critical analysis. Can J Phys 58: 1200-1211.
81. Becke AD, (1993) Density-functional thermochemistry III. The role of exact exchange. J Chem Phys 98: 5648-5652.
82. Stephens P, Devlin F, Chabalowski C, Frisch M, (1994) Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields. J Phys Chem 98: 11623-11627.
83. Hay PJ, Wadt WR, (1985) Ab initio effective core potentials for molecular calculations. Potentials for k to au including the outermost core orbitals. J Chem Phys 82: 299-310.
84. Rassolov V, Ratner M, Pople J, Redfern P, Curtiss L, (2001) 6-31G* basis set for third-row atoms. J Comput Chem 22: 976-984.
85. Grimme S, (2006) Semiempirical GGA-type density functional constructed with a long-range dispersion correction. J Comput Chem 27: 1787-1799.