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Pressure‐induced structural transition of mature HIV ‐1 protease from a combined NMR/MD simulation approach
Author(s) -
Roche Julien,
Louis John M.,
Bax Ad,
Best Robert B.
Publication year - 2015
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24931
Subject(s) - chemistry , dimer , residual dipolar coupling , hiv 1 protease , molecular dynamics , metastability , protease , crystallography , biophysics , nuclear magnetic resonance spectroscopy , stereochemistry , enzyme , biochemistry , computational chemistry , organic chemistry , biology
ABSTRACT We investigate the pressure‐induced structural changes in the mature human immunodeficiency virus type 1 protease dimer, using residual dipolar coupling (RDC) measurements in a weakly oriented solution. 1 D NH RDCs were measured under high‐pressure conditions for an inhibitor‐free PR and an inhibitor‐bound complex, as well as for an inhibitor‐free multidrug resistant protease bearing 20 mutations (PR20). While PR20 and the inhibitor‐bound PR were little affected by pressure, inhibitor‐free PR showed significant differences in the RDCs measured at 600 bar compared with 1 bar. The structural basis of such changes was investigated by MD simulations using the experimental RDC restraints, revealing substantial conformational perturbations, specifically a partial opening of the flaps and the penetration of water molecules into the hydrophobic core of the subunits at high pressure. This study highlights the exquisite sensitivity of RDCs to pressure‐induced conformational changes and illustrates how RDCs combined with MD simulations can be used to determine the structural properties of metastable intermediate states on the folding energy landscape. Proteins 2015; 83:2117–2123. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.