Document Detail

Denaturation of HIV-1 Protease (PR) Monomer by Acetic Acid: Mechanistic and Trajectory Insights from Molecular Dynamics Simulations and NMR.
MedLine Citation:
PMID:  22292950     Owner:  NLM     Status:  In-Data-Review    
Inside a living cell there can be a variety of interactions for any given protein, which serve to regulate denaturation and renaturation processes. Insights into some of them can be obtained by in vitro studies using various denaturing agents. In this study, all-atom MD simulations in explicit solvent and NMR relaxation studies were performed on HIV-1 Protease (PR) in 9 M acetic acid (AcOH) (the commonly used denaturant during PR preparation). Following previous reports that denaturation proceeds via dissociation of the dimer into monomers, unfolding of the monomer by acetic acid has been explicitly investigated here. Direct visualization of the denaturation process and evidence for the mechanism of denaturation have been presented. Our simulations reveal that the denaturation of the PR monomer is caused due to direct interaction between acetic acid molecules and PR. Autocorrelation of N-H vectors calculated from the simulations have revealed that the α-helix and the surrounding β-strands represent the sensitive regions of the PR that respond maximally to the change in the solvent environment around the PR and are prone to disruption by acetic acid. This disruption is caused due to increased penetration of the acetic acid molecules into the PR structure by formation of preferred tertiary contacts and hydrogen bonds between the PR and acetic acid molecules. Following the loss of these critical interactions, the PR follows a random and non-equilibrating path on the conformation landscape and cycles between different denatured extended and compact states.
A Borkar; M K Rout; R V Hosur
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of biomolecular structure & dynamics     Volume:  29     ISSN:  1538-0254     ISO Abbreviation:  J. Biomol. Struct. Dyn.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-02-01     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8404176     Medline TA:  J Biomol Struct Dyn     Country:  United States    
Other Details:
Languages:  eng     Pagination:  893-903     Citation Subset:  IM    
Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai-400005, India.
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