Influence of the membrane lipophilic environment on the structure and on the substrate access/egress routes of the human aromatase enzyme. A computational study

Journal of Chemical Information and Modeling

Volumn 52, Issue 6, 2012, Pages 1595-1606

  Sgrignani, Jacopo ^a   Magistrato, Alessandra ^a  

^a DEMOCRITOS NATIONAL SIMULATION CENTER   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

BIOCHEMISTRY; COMPUTATIONAL CHEMISTRY; ENZYMES; MEDICINE; MOLECULAR DYNAMICS;

ATOMISTIC MODELING; COMPUTATIONAL STUDIES; COMPUTATIONAL TECHNIQUE; DYNAMICAL PROPERTIES; MEMBRANE ANCHORING; MEMBRANE MODELING; MOLECULAR DYNAMICS SIMULATIONS; SUBSTRATE SELECTIVITY;

MEMBRANES;

AROMATASE; MEMBRANE LIPID;

ARTICLE; CHEMICAL STRUCTURE; CHEMISTRY; ENZYME ACTIVE SITE; ENZYME SPECIFICITY; METABOLISM; MOLECULAR DYNAMICS; PROTEIN CONFORMATION;

AROMATASE; CATALYTIC DOMAIN; MEMBRANE LIPIDS; MODELS, MOLECULAR; MOLECULAR DYNAMICS SIMULATION; PROTEIN CONFORMATION; SUBSTRATE SPECIFICITY;

EID: 84862907043     PISSN: 15499596     EISSN: 1549960X     Source Type: Journal    
DOI: 10.1021/ci300151h     Document Type: Article

References (100)

1. Kumar, S. Engineering cytochrome P450 biocatalysts for biotechnology, medicine and bioremediation Expert Opin. Drug Metab. Toxicol. 2010, 6, 115-131
2. Hong, Y.; Li, H.; Ye, J.; Miki, Y.; Yuan, Y.-C.; Sasano, H.; Evans, D. B.; Chen, S. Epitope Characterization of an Aromatase Monoclonal Antibody Suitable for the Assessment of Intratumoral Aromatase Activity PLoS One 2009, 4, e8050
3. Czajka-Oraniec, I.; Simpson, E. R. Aromatase research and its clinical significance Endokrynol. Pol. 2010, 61, 126-134
4. Santen, R. J.; Brodie, H.; Simpson, E. R.; Siiteri, P. K.; Brodie, A. History of aromatase: saga of an important biological mediator and therapeutic target Endocr. Rev. 2009, 30, 343-375
5. Altundag, K.; Ibrahim, N. K. Aromatase Inhibitors in Breast Cancer: An Overview The Oncologist 2006, 11, 553-562
6. Jones, M. E. E.; Boon, W. C.; McInnes, K.; Maffei, L.; Carani, C.; Simpson, E. R. Recognizing rare disorders: aromatase deficiency Nat. Clin. Pract. Endocrinol. Metab. 2007, 3, 414-421
7. Saldanha, C. J.; Duncan, K. A.; Walters, B. J. Neuroprotective actions of brain aromatase Front. Neuroendocrinol. 2009, 30, 106-118
8. Garcia-Segura, L. M.; Veiga, S.; Sierra, A.; Melcangi, R. C.; Azcoitia, I. Aromatase: a neuroprotective enzyme Prog. Neurobiol. 2003, 71, 31-41
9. Laville, N.; Balaguer, P.; Brion, F.; Hinfray, N.; Casellas, C.; Porcher, J.-M.; Ait-Aissa, S. Modulation of aromatase activity and mRNA by various selected pesticides in the human choriocarcinoma JEG-3 cell line Toxicology 2006, 228, 98-9108
10. Banting, L.; Ahmed, S. Aromatase: the enzyme and its inhibition Anticancer Agents Med. Chem. 2009, 9, 627-641
11. Lala, P.; Higashiyama, T.; Erman, M.; Griswold, J.; Wagner, T.; Osawa, Y.; Ghosh, D. Suppression of human cytochrome P450 aromatase activity by monoclonal and recombinant antibody fragments and identification of a stable antigenic complex J. Steroid Biochem. Mol. Biol. 2004, 88, 235-245
12. Ghosh, D.; Griswold, J.; Erman, M.; Pangborn, W. Structural basis for androgen specificity and oestrogen synthesis in human aromatase Nature 2009, 457, 219-223
13. Maurelli, S.; Chiesa, M.; Giamello, E.; Di Nardo, G.; Ferrero, V. E.; Gilardi, G.; Van Doorslaer, S. Direct spectroscopic evidence for binding of anastrozole to the iron heme of human aromatase. Peering into the mechanism of aromatase inhibition Chem. Commun. 2011, 47, 10737-10379
14. Graham-Lorence, S.; Khalil, M. W.; Lorence, M. C.; Mendelson, C. R.; Simpson, E. R. Structure-function relationships of human aromatase cytochrome P-450 using molecular modeling and site-directed mutagenesis J. Biol. Chem. 1991, 266, 11939-11946
15. Koymans, L. M. H.; Moereels, H.; Vanden Bossche, H. A molecular model for the interaction between vorozole and other non-steroidal inhibitors and human cytochrome P450 19 (P450 aromatase) J. Steroid Biochem. Mol. Biol. 1995, 53, 191-197
16. Laughton, C. A.; Zvelebil, M. J.; Neidle, S. A detailed molecular model for human aromatase J. Steroid Biochem. Mol. Biol. 1993, 44, 399-407
17. Graham-Lorence, S.; Amarneh, B.; White, R. E.; Peterson, J. A.; Simpson, E. R. A three-dimensional model of aromatase cytochrome P450 Protein Sci. 1995, 4, 1065-1080
18. Chen, S.; Kao, Y. C.; Laughton, C. A. Binding characteristics of aromatase inhibitors and phytoestrogens to human aromatase J. Steroid Biochem. Mol. Biol. 1997, 61, 107-115
19. Lewis, D. F. V.; Lee-Robichaud, P. Molecular modelling of steroidogenic cytochromes P450 from families CYP11, CYP17, CYP19 and CYP21 based on the CYP102 crystal structure J. Steroid Biochem. Mol. Biol. 1998, 66, 217-233
20. Chen, S.; Zhang, F.; Sherman, M. A.; Kijima, I.; Cho, M.; Yuan, Y. C.; Toma, Y.; Osawa, Y.; Zhou, D.; Eng, E. T. Structure-function studies of aromatase and its inhibitors: A progress report J. Steroid Biochem. Mol. Biol. 2003, 86, 231-237
21. Loge, C.; Le Borgne, M.; Marchand, P.; Robert, J. M.; Le Baut, G.; Palzer, M.; Hartmann, R. W. Three-dimensional model of cytochrome P450 human aromatase J. Enzyme Inhib. Med. Chem. 2005, 20, 581-585
22. Favia, A. D.; Cavalli, A.; Masetti, M.; Carotti, A.; Recanatini, M. Three-dimensional model of the human aromatase enzyme and density functional parameterization of the iron-containing protoporphyrin IX for a molecular dynamics study of heme-cysteinato cytochromes Proteins: Struct., Funct. Bioinf. 2006, 62, 1074-1087
23. Karkola, S.; Höltje, H. D.; Wähälä, K. A three-dimensional model of CYP19 aromatase for structure-based drug design J. Steroid Biochem. Mol. Biol. 2007, 105, 63-70
24. Conner, K. P.; Woods, C. M.; Atkins, W. M. Interactions of cytochrome P450s with their ligands Arch. Biochem. Biophys. 2011, 507, 56-65
25. Denisov, I. G.; Makris, T. M.; Sligar, S. G.; Schlichting, I. Structure and Chemistry of Cytochrome P450 Chem. Rev. 2005, 105, 2253-2278
26. Cojocaru, V.; Winn, P. J.; Wade, R. C. The ins and outs of cytochrome P450s Biochim. Biophys. Acta 2007, 1770, 390-401
27. Cojocaru, V.; Balali-Mood, K.; Sansom, M. S. P.; Wade, R. C. Structure and Dynamics of the Membrane-Bound Cytochrome P450 2C9 PLoS Comput. Biol. 2011, 7, e1002152
28. Berka, K.; Hendrychova, T.; Anzenbacher, P.; Otyepka, M. Membrane Position of Ibuprofen Agrees with Suggested Access Path Entrance to Cytochrome P450 2C9 Active Site J. Phys. Chem. A 2011, 115, 11248-11255
29. Denisov, I. G.; Shih, A. Y.; Sligar, S. G. Structural differences between soluble and membrane bound cytochrome P450s J. Inorg. Biochem. 2011, 108, 150-158
30. Otyepka, M.; Berka, K.; Anzenbacher, P. Is there a relationship between the substrate preferences and structural flexibility of cytochromes p450? Curr. Drug Metab. 2012, 13, 130-142
31. Schleinkofer, K.; Sudarko; Winn, P. J.; Ludemann, S. K.; Wade, R. C. Do mammalian cytochrome P450s show multiple ligand access pathways and ligand channelling? EMBO Rep. 2005, 6, 584-589
32. Wade, R. C.; Winn, P. J.; Schlichting, I.; Sudarko A survey of active site access channels in cytochromes P450 J. Inorg. Biochem. 2004, 98, 1175-1182
33. Ludemann, S. K.; Lounnas, V.; Wade, R. C. How do substrates enter and products exit the buried active site of cytochrome P450cam? 2. Steered molecular dynamics and adiabatic mapping of substrate pathways J. Mol. Biol. 2000, 303, 813-830
34. Winn, P. J.; Ludemann, S. K.; Gauges, R.; Lounnas, V.; Wade, R. C. Comparison of the dynamics of substrate access channels in three cytochrome P450s reveals different opening mechanisms and a novel functional role for a buried arginine Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 5361-5366
35. Yaffe, E.; Fishelovitch, D.; Wolfson, H. J.; Halperin, D.; Nussinov, R. MolAxis: efficient and accurate identification of channels in macromolecules Proteins: Struct., Funct., Bioinf. 2008, 73, 72-86
36. Krishnamoorthy, N.; Gajendrarao, P.; Thangapandian, S.; Lee, Y.; Lee, K. W. Probing possible egress channels for multiple ligands in human CYP3A4: a molecular modeling study J. Mol. Model. 2010, 16, 607-614
37. Li, W.; Shen, J.; Liu, G.; Tang, Y.; Hoshino, T. Exploring coumarin egress channels in human cytochrome p450 2a6 by random acceleration and steered molecular dynamics simulations Proteins: Struct., Funct., Bioinf. 2011, 79, 271-281
38. Skopalik, J.; Anzenbacher, P.; Otyepka, M. Flexibility of Human Cytochromes P450: Molecular Dynamics Reveals Differences between CYPs 3A4, 2C9, and 2A6, which Correlate with Their Substrate Preferences J. Phys. Chem. B 2008, 112, 8165-8173
39. Cojocaru, V.; Winn, P. J.; Wade, R. C. Multiple, ligand-dependent routes from the active site of cytochrome P450 2C9 Curr. Drug Metab. 2011, 13, 143-154
40. Branduardi, D.; Gervasio, F. L.; Cavalli, A.; Recanatini, M.; Parrinello, M. The role of the peripheral anionic site and cation-pi interactions in the ligand penetration of the human AChE gorge J. Am. Chem. Soc. 2005, 127, 9147-9155
41. Shen, J.; Li, W.; Liu, G.; Tang, Y.; Jiang, H. Computational insights into the mechanism of ligand unbinding and selectivity of estrogen receptors J. Phys. Chem. B 2009, 113, 10436-10444
42. Lindahl, E.; Sansom, M. S. P. Membrane proteins: molecular dynamics simulations Curr. Opin. Struct. Biol. 2008, 18, 425-431
43. Tozzini, V. Multiscale modeling of proteins Acc. Chem. Res. 2009, 43, 220-230
44. Kandt, C.; Ash, W. L.; Tieleman, P. D. Setting up and running molecular dynamics simulations of membrane proteins Methods 2007, 41, 475-488
45. Amarneh, B.; Corbin, C. J.; Peterson, J. A.; Simpson, E. R.; Graham-Lorence, S. Functional domains of human aromatase cytochrome P450 characterized by linear alignment and site-directed mutagenesis Mol. Endocrinol. 1993, 7, 1617-1624
46. Auvray, P.; Nativelle, C.; Bureau, R.; Dallemagne, P.; Seralini, G. E.; Sourdaine, P. Study of substrate specificity of human aromatase by site directed mutagenesis Eur. J. Biochem. 2002, 269, 1393-1405
47. Zhou, D.; Cam, L. L.; Laughton, C. A.; Korzekwa, K. R.; Chen, S. Mutagenesis study at a postulated hydrophobic region near the active site of aromatase cytochrome P450 J. Biol. Chem. 1994, 269, 19501-19508
48. Zhou, D. J.; Pompon, D.; Chen, S. A. Structure-function studies of human aromatase by site-directed mutagenesis: kinetic properties of mutants Pro-308 - - Phe, Tyr-361 - - Phe, Tyr-361 - - Leu, and Phe-406 - - Arg Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 410-414
49. Zhou, D. J.; Korzekwa, K. R.; Poulos, T.; Chen, S. A. A site-directed mutagenesis study of human placental aromatase J. Biol. Chem. 1992, 267, 762-768
50. Conley, A.; Mapes, S.; Corbin, C. J.; Greger, D.; Graham, S. Structural determinants of aromatase cytochrome p450 inhibition in substrate recognition site-1 Mol. Endocrinol. 2002, 16, 1456-1468
51. Kao, Y. C.; Zhou, C.; Sherman, M.; Laughton, C. A.; Chen, S. Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study Environ. Health Perspect. 1998, 106, 85-92
52. Kao, Y. C.; Korzekwa, K. R.; Laughton, C. A.; Chen, S. Evaluation of the mechanism of aromatase cytochrome P450. A site-directed mutagenesis study Eur. J. Biochem. 2001, 268, 243-251
53. Kao, Y. C.; Cam, L. L.; Laughton, C. A.; Zhou, D.; Chen, S. Binding characteristics of seven inhibitors of human aromatase: a site-directed mutagenesis study Cancer Res. 1996, 56, 3451-3460
54. Simona, F.; Magistrato, A.; Vera, D. M. A.; Garau, G.; Vila, A. J.; Carloni, P. Protonation state and substrate binding to B2 metallo-beta-lactamase CphA from Aeromonas hydrofila Proteins: Struct., Funct., Bioinf. 2007, 69, 595-605
55. Hong, R.; Magistrato, A.; Carloni, P. Anthrax Lethal Factor Investigated by Molecular Simulations J. Chem. Theory Comput. 2008, 4, 1745-1756
56. Case, D. A.; Darden, T. A.; Cheatham, T. E., III; Simmerling, C. L.; Wang, J.; Duke, R. E.; Luo, R.; Walker, R. C.; Zhang, W.; Merz, K. M.; Roberts, B.; Wang, B.; Hayik, S.; Roitberg, A.;; Seabra, G.; Kolossváry, I.; Wong, K. F.; Paesani, F.; Vanicek, J.; Liu, J.; Wu, X.; Brozell, R. R.;; Steinbrecher, T.; Gohlke, H.; Cai, Q.; Ye, X.; Wang, J.; Hsieh, M. J.; Cui, G.; Roe, D. R.; Mathews, D. H.; Seetin, M. G.; Sagui, C.; Babin, V.; Luchko, T.; Gusarov, S.; Kovalenko, A.;; Kollman, P. A. AMBER11; University of California: San Francisco, CA, 2010.
57. Carnevale, V.; Fiorin, G.; Levine, B. G.; Degrado, W. F.; Klein, M. L. Multiple Proton Confinement in the M2 Channel from the Influenza A Virus J. Phys. Chem. C 2010, 114, 20856-20863
58. Guex, N.; Peitsch, M. C. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling Electrophoresis 1997, 18, 2714-2723
59. Shimozawa, O.; Sakaguchi, M.; Ogawa, H.; Harada, N.; Mihara, K.; Omura, T. Core glycosylation of cytochrome P-450(arom). Evidence for localization of N terminus of microsomal cytochrome P-450 in the lumen J. Biol. Chem. 1993, 268, 21399-21402
60. Humphrey, W.; Dalke, A.; Schulten, K. VMD: visual molecular dynamics J. Mol. Graphics 1996, 14, 33-38
61. Jojart, B.; Martinek, T. A. Performance of the general amber force field in modeling aqueous POPC membrane bilayers J. Comput. Chem. 2007, 28, 2051-2058
62. Duan, Y.; Wu, C.; Chowdhury, S.; Lee, M. C.; Xiong, G.; Zhang, W.; Yang, R.; Cieplak, P.; Luo, R.; Lee, T.; Caldwell, J.; Wang, J.; Kollman, P. A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations J. Comput. Chem. 2003, 24, 1999-2012
63. Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, L. M. Comparison of simple potential functions for simulating liquid water J. Chem. Phys. 1983, 79, 926-935
64. Aaqvist, J. Ion-water interaction potentials derived from free energy perturbation simulations J. Chem. Phys. 1990, 94, 8021-8024
65. Giammona, D. A. Ph.D. Thesis, University of California Davis, CA, 1984.
66. Wang, J.; Wolf, R. M.; Caldwell, J. W.; Kollman, P. A.; Case, D. A. Development and testing of a general amber force field J. Comput. Chem. 2004, 25, 1157-1174
67. Bayly, C. I.; Cieplak, P.; Cornell, W. D.; Kollman, P. A. A well-behaved electrostatic potential based method using charge restraints for determining atom-centered charges: the RESP model J. Phys. Chem. 1993, 97, 10269-10280
68. Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Kollmann, P. A. Application of RESP charges to calculate conformational energies, hydrogen bond energies, and free energies of solvation J. Am. Chem. Soc. 1993, 115, 9620-9631
69. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Laham, A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision C.02; 2003.
70. Sgrignani, J.; Magistrato, A. The structural role of mg(2+) ions in a class I RNA polymerase ribozyme: a molecular simulation study J. Phys. Chem. B 2012, 116, 2259-2268
71. Vargiu, A. V.; Magistrato, A. Detecting DNA mismatches with metallo-insertors: a molecular simulation study Inorg. Chem. 2012, 51, 2046-2057
72. Gantt, S. L.; Denisov, I. G.; Grinkova, Y. V.; Sligar, S. G. The critical iron-oxygen intermediate in human aromatase Biochem. Biophys. Res. Commun. 2009, 387, 169-173
73. Phillips, J. C.; Braun, R.; Wang, W.; Gumbart, J.; Tajkhorshid, E.; Villa, E.; Chipot, C.; Skeel, R. D.; Kale, L.; Schulten, K. Scalable molecular dynamics with NAMD J. Comput. Chem. 2005, 26, 1781-1802
74. Martyna, G.; Tobias, D.; Klein, M. Constant pressure molecular dynamics algorithms J. Chem. Phys. 1994, 101, 4177-4189
75. Feller, S.; Zhang, Y.; Pastor, R.; Brooks, B. Constant pressure molecular dynamics simulation: The Langevin piston method J. Chem. Phys. 1995, 103, 4613-4621
76. Shao, J.; Tanner, S. W.; Thompson, N.; Cheatham, T. E. Clustering Molecular Dynamics Trajectories: 1. Characterizing the Performance of Different Clustering Algorithms J. Chem. Theory Comput. 2007, 3, 2312-2334
77. 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 Bioinf. 2006, 7, 316-316
78. Dijkstra, E. W. A note on two problems in connexion with graphs Numerische Math. 1959, 1, 269-271
79. The PyMOL Molecular Graphics System, V. r. p., Schrödinger, LLC: The PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, LLC.
80. Vashisth, H.; Abrams, C. F. Ligand escape pathways and (un)binding free energy calculations for the hexameric insulin-phenol complex Biophys. J. 2008, 95, 4193-4204
81. Colizzi, F.; Perozzo, R.; Scapozza, L.; Recanatini, M.; Cavalli, A. Single-molecule pulling simulations can discern active from inactive enzyme inhibitors J. Am. Chem. Soc. 2010, 132, 7361-7371
82. Yang, L.-J.; Zou, J.; Xie, H.-Z.; Li, L.-L.; Wei, Y.-Q.; Yang, S.-Y. Steered molecular dynamics simulations reveal the likelier dissociation pathway of imatinib from its targeting kinases c-Kit and Abl PLoS One 2009, 4, e8470
83. Cohen, J.; Arkhipov, A.; Braun, R.; Schulten, K. Imaging the migration pathways for O2, CO, NO, and Xe inside myoglobin Biophys. J. 2006, 91, 1844-1857
84. Cohen, J.; Schulten, K. O2 Migration Pathways Are Not Conserved across Proteins of a Similar Fold Biophys. J. 2007, 93, 3591-3600
85. Cohen, J.; Olsen, K. W.; Schulten, K. Finding gas migration pathways in proteins using implicit ligand sampling Methods Enzymol. 2008, 437, 439-457
86. Forti, F.; Boechi, L.; Estrin, D. A.; Marti, M. A. Comparing and combining implicit ligand sampling with multiple steered molecular dynamics to study ligand migration processes in heme proteins J. Comput. Chem. 2011, 32, 2219-2231
87. Forti, F.; Boechi, L.; Bikiel, D.; Marti, M. A.; Nardini, M.; Bolognesi, M.; Viappiani, C.; Estrin, D. O.; Luque, F. J. Ligand Migration in Methanosarcina acetivorans Protoglobin: Effects of Ligand Binding and Dimeric Assembly J. Phys. Chem. B 2011, 115, 13771-13780
88. Bayburt, T. H.; Sligar, S. G. Single-molecule height measurements on microsomal cytochrome P450 in nanometer-scale phospholipid bilayer disks Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 6725-6730
89. Kadohama, N.; Yarborough, C.; Zhou, D.; Chen, S.; Osawa, Y. Kinetic properties of aromatase mutants Pro308Phe, Asp309Asn, and Asp309Ala and their interactions with aromatase inhibitors J. Steroid. Biochem. Mol. Biol. 1992, 43, 693-701
90. Di Nardo, G.; Breitner, M.; Sadeghi, S. J.; Nicolai, E.; Mei, G.; Bandino, A.; Ghosh, D.; Panzica, G.; Gilardi, G. A pH-dependent structural rearrangement of the human aromatase active site: implications in catalysis FEBS J. 2010, 277, 175-175
91. Arroyo-Manez, P.; Bikiel, D. n. E.; Boechi, L.; Capece, L.; Di Lella, S.; Estrin, D. A.; MartÌ, M. A.; Moreno, D. M.; Nadra, A. D.; Petruk, A. A. Protein dynamics and ligand migration interplay as studied by computer simulation Biochim. Biophys. Acta 2011, 1814, 1054-1064
92. Scorciapino, M. A.; Robertazzi, A.; Casu, M.; Ruggerone, P.; Ceccarelli, M. Heme proteins: the role of solvent in the dynamics of gates and portals J. Am. Chem. Soc. 2010, 132, 5156-5163
93. Carrillo, O.; Orozco, M. GRID-MD-A tool for massive simulation of protein channels Proteins: Struct., Funct., Bioinf. 2008, 70, 892-899
94. Otyepka, M.; SkopalÌk, J.; Anzenbacherov, E.; Anzenbacher, P. What common structural features and variations of mammalian P450s are known to date? Biochim. Biophys. Acta 2007, 1770, 376-389
95. Sgrignani, J.; Bonaccini, C.; Grazioso, G.; Chioccioli, M.; Cavalli, A.; Gratteri, P. Insights into docking and scoring neuronal alpha4beta2 nicotinic receptor agonists using molecular dynamics simulations and QM/MM calculations J. Comput. Chem. 2009, 30, 2443-2454
96. Amaro, R. E.; Baron, R.; McCammon, J. A. An improved relaxed complex scheme for receptor flexibility in computer-aided drug design J. Comput.-Aided Mol. Des. 2008, 22, 693-705
97. Fishelovitch, D.; Shaik, S.; Wolfson, H. J.; Nussinov, R. 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 2009, 113, 13018-13025
98. Jarzynski, C. Nonequilibrium Equality for Free Energy Differences Phys. Rev. Lett. 1997, 78, 2690-2693
99. Wang, Y.; Cohen, J.; Boron, W. F.; Schulten, K.; Tajkhorshid, E. Exploring gas permeability of cellular membranes and membrane channels with molecular dynamics J. Struct. Biol. 2007, 157, 534-544
100. Jiang, W.; Ghosh, D. Motion and Flexibility in Human Cytochrome P450 Aromatase PLoS One 2012, 7 (2) e32565