Pressure-induced structural transition of mature HIV-1 Protease from a combined NMR/MD simulation approach.
 

Pressure-induced structural transition of mature HIV-1 Protease from a combined NMR/MD simulation approach.

Related Articles Pressure-induced structural transition of mature HIV-1 Protease from a combined NMR/MD simulation approach.

Proteins. 2015 Sep 18;

Authors: Roche J, Louis JM, Bax A, Best RB

Abstract
We investigate the pressure-induced structural changes in the mature human immunodeficiency virus type 1 protease dimer (HIV-1 PR), using residual dipolar coupling (RDC) measurements in a weakly oriented solution. (1) DNH 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 to 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. This article is protected by copyright. All rights reserved.


PMID: 26385843 [PubMed - as supplied by publisher]



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