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Accurate prediction of protonation state as a prerequisite for reliable MM‐PB(GB)SA binding free energy calculations of HIV‐1 protease inhibitors
Author(s) -
Wittayanarakul Kitiyaporn,
Hangbua Supot,
Feig Michael
Publication year - 2007
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.20821
Subject(s) - protonation , amprenavir , chemistry , indinavir , saquinavir , lopinavir , hiv 1 protease , affinities , computational chemistry , nelfinavir , protease , binding energy , molecular dynamics , stereochemistry , enzyme , human immunodeficiency virus (hiv) , biochemistry , organic chemistry , medicine , ion , physics , sida , family medicine , viral disease , antiretroviral therapy , viral load , nuclear physics
Binding free energies were calculated for the inhibitors lopinavir, ritonavir, saquinavir, indinavir, amprenavir, and nelfinavir bound to HIV‐1 protease. An MMPB/SA‐type analysis was applied to conformational samples from 3 ns explicit solvent molecular dynamics simulations of the enzyme‐inhibitor complexes. Binding affinities and the sampled conformations of the inhibitor and enzyme were compared between different HIV‐1 protease protonation states to find the most likely protonation state of the enzyme in the complex with each of the inhibitors. The resulting set of protonation states leads to good agreement between calculated and experimental binding affinities. Results from the MMPB/SA analysis are compared with an explicit/implicit hybrid scheme and with MMGB/SA methods. It is found that the inclusion of explicit water molecules may offer a slight advantage in reproducing absolute binding free energies while the use of the Generalized Born approximation significantly affects the accuracy of the calculated binding affinities. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008