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Drug resistance in HIV‐1 protease: Flexibility‐assisted mechanism of compensatory mutations
Author(s) -
Piana Stefano,
Carloni Paolo,
Rothlisberger Ursula
Publication year - 2002
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 - 10.1110/ps.0206702
Subject(s) - active site , enzyme , mutation , mechanism (biology) , protease , molecular dynamics , flexibility (engineering) , chemistry , substrate (aquarium) , hiv 1 protease , biology , genetics , biophysics , biochemistry , gene , computational chemistry , ecology , philosophy , statistics , mathematics , epistemology
The emergence of drug‐resistant variants is a serious side effect associated with acquired immune deficiency syndrome therapies based on inhibition of human immunodeficiency virus type 1 protease (HIV‐1 PR). In these variants, compensatory mutations, usually located far from the active site, are able to affect the enzymatic activity via molecular mechanisms that have been related to differences in the conformational flexibility, although the detailed mechanistic aspects have not been clarified so far. Here, we perform multinanosecond molecular dynamics simulations on L63P HIV‐1 PR, corresponding to the wild type, and one of its most frequently occurring compensatory mutations, M46I, complexed with the substrate and an enzymatic intermediate. The quality of the calculations is established by comparison with the available nuclear magnetic resonance data. Our calculations indicate that the dynamical fluctuations of the mutated enzyme differ from those in the wild type. These differences in the dynamic properties of the adducts with the substrate and with the gem‐diol intermediate might be directly related to variations in the enzymatic activity and therefore offer an explanation of the observed changes in catalytic rate between wild type and mutated enzyme. We anticipate that this “flexibility‐assisted” mechanism might be effective in the vast majority of compensatory mutations, which do not change the electrostatic properties of the enzyme.