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Molecular mechanisms of resistance: Free energy calculations of mutation effects on inhibitor binding to HIV‐1 protease
Author(s) -
Rick Steven W.,
Topol Igor A.,
Burt Stanley K.,
Erickson John W.
Publication year - 1998
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.5560070809
Subject(s) - hiv 1 protease , indinavir , saquinavir , protease , molecular dynamics , mutation , chemistry , valine , isoleucine , biophysics , enzyme , stereochemistry , biochemistry , biology , leucine , computational chemistry , genetics , amino acid , virus , gene , antiretroviral therapy , sida , viral disease , viral load
The changes in the inhibitor binding constants due to the mutation of isoleucine to valine at position 84 of HIV‐1 protease are calculated using molecular dynamics simulations. The calculations are done for three potent inhibitors‐KNI‐272, L‐735,524 (indinavir or MK‐639), and Ro 31‐8959 (saquinavir). The calculations agree with the experimental data both in terms of an overall trend and in the magnitude of the resulting free energy change. HIV‐1 protease is a homodimer, so each mutation causes two changes in the enzyme. The decrease in the binding free energy from each mutated side chain differs among the three inhibitors and correlates well with the size of the cavities induced in the protein interior near the mutated residue. The cavities are created as a result of a mutation to a smaller side chain, but the cavities are less than would be predicted from the wild‐type structures, indicating that there is significant relaxation to partially fill the cavities.