Bulletin of the Korean Chemical Society

  • 제21권12호
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  • Pages.1207-1212
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  • 2000
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  • 0253-2964(pISSN)
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  • 1229-5949(eISSN)
대한화학회 (Korean Chemical Society)
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Binding Free Energy Simulations of the HIV-1 Protease and Hydroxyethylene Isostere Inhibitors

  • 발행 : 20001200
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초록

The free energy simulation technique is used to evaluate the relative binding affinity of a set of hydroxyethylene isostere inhibitors of the HIV-1 protease. The binding reactions and an alchemical mutation construct the thermodynamic cycle, which reduces the free energy difference of the binding interactions into that of the alchemical processes. In the alchemical process, a methyl group is mutated into a hydrogen atom. Albeit the change is a small perturbation to the inhibitor-protease complex, it results in 25 fold difference in the binding constants. The simulation reproduces the experimentally measured binding affinities within 2% of the free energy difference. The protonation state of the catalytic aspartic acid residues is also investigated through the free energy simulations.

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참고문헌

  1. Ann. Rev. Biochem. no.57 Krausslich, H. G.;Wimmer, E.
  2. Ann. Rev. Biochem. no.62 Wlodawer, A.;Erickson, J. W.
  3. Accounts Chem. Res. no.27 Kuntz, I. D.;Meng, E. C.;Shoichet, B. K.
  4. Biochemis-try no.30 Hyland, L. J.;Tomasek Jr., T. A.;Meek, T. D.
  5. J. Chem. Inf. Computer Sci. no.33 Goldblum, A.;Rayan, A.;Fliess, A.;Glick, M.
  6. Proteins: A Theoretical Perspective of Dynamics, Structure, and Ther-modynamics Adv. Chem. Phys. LXXI Brooks III, C. L.;Karplus, M.;Pettitt, B. M.
  7. Ann. Rev. Phys. Chem. no.43 McCammon, J. A.;Straatsma, T. P.
  8. Chem. Rev. no.93 Kollman, P. A.
  9. J. Med. Chem. no.38 Chen, X.;Tropsha, A.
  10. Proc. Natl. Acad. Sci. no.88 Reddy, M. R.;Viswanadhan, V. N.;Weinstein, J. N.
  11. Protein Eng. no.51 Tropsha, A.;Hermans, J.
  12. J. Med. Chem. no.34 Ferguson, D. M.;Radmer, R. J.;Kollman, P. A.
  13. J. Med. Chem. no.34 Rich, D. H.;Sun, C.;Vara-Prasad, J. V.;Pathiasseril, A.;Toth, M. V.;Marshall, G. R.;Clare, M.;Mueller, R. A.;Houseman, K.
  14. Biochemistry no.30 Jaskolski, M.;Tomasselli, A. G.;Sawyer, T. K.;Staples, D. G.; Heinrikson, R. L.; Schneider, J.; Kent, S. B.;Wlodawer, A.
  15. J. Am. Chem. Soc. no.117 Charfield, D. C.;Broks, B. R.
  16. J. Am. Chem. Soc. no.113 Swaminathan, S.;Harte, W. E.;Beveridge, D. L.
  17. J. Am. Chem. Soc. no.115 Harte, W. E.;Berveridge, D. L.
  18. Biochemistry no.32 York, D. M.;Darden, T. A.;Pedersen, L. G.;Anderson, M. W.
  19. Biochemistry no.31 Dryer, G. B.;Lambert, D. M.;Meek, T. D.;Carr, T. J.;Tomaszek Jr., T. A.;Fernamdez, A. V.;Bartus, H.;Caccia-villani, E.;Hassell, A. M.;Minnich, M.;Petteway Jr., S. R.;Metcalf, B. W.
  20. J. Comput. Chem. no.4 Brooks, S. R.;Bruccoleir, R. E.;Olafson, B. D.;States, D. J.;Swaminathan, S.;Karplus, M.
  21. Encyclopedia of Computational Chemistry MacKerell Jr., A. D.; Brooks, B.; Brooks III, C. L.; Nils-son, N.; Roux, B.; Won, Y.; Karplus, M.;van Ragu Schleyer, P.(ed.);Allinger, N. L.(ed.);Kollman, P. A.(ed.);Clark, T.(ed.);Schaefer III, H. F.(ed.);Gasteiger, J.
  22. Statistical Mechanics McQuarrie, D. A.
  23. Biochemistry Voet, D.;Voet, J. G.

피인용 문헌

  1. The pKa Shift of the Catalytic Aspartyl Dyad in the HIV-1 Protease Complexed with Hydroxyethylene Inhibitors vol.23, pp.1, 2002, https://doi.org/10.5012/bkcs.2002.23.1.027
  2. Investigation of the Protonated State of HIV-1 Protease Active Site vol.24, pp.6, 2003, https://doi.org/10.5012/bkcs.2003.24.6.817
  3. Structural and dynamical properties of different protonated states of mutant HIV-1 protease complexed with the saquinavir inhibitor studied by molecular dynamics simulations vol.25, pp.3, 2000, https://doi.org/10.1016/j.jmgm.2006.01.004