Drug‐resistant HIV‐1 protease regains functional dynamics through cleavage site coevolution

Evolutionary Applications

Nevra Özer²  Ayᗾgül Özen¹  Celia A. Schiffer¹ 

[1] Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA;Polymer Research Center and Chemical Engineering Department, Bogazici University, Bebek, Istanbul, Turkey

关键词: coevolution;    elastic network model;    fluctuations;    HIV‐1 protease;   

DOI  :  10.1111/eva.12241

来源: Wiley

【 摘 要 】

Abstract

Drug resistance is caused by mutations that change the balance of recognition favoring substrate cleavage over inhibitor binding. Here, a structural dynamics perspective of the regained wild-type functioning in mutant HIV-1 proteases with coevolution of the natural substrates is provided. The collective dynamics of mutant structures of the protease bound to p1-p6 and NC-p1 substrates are assessed using the Anisotropic Network Model (ANM). The drug-induced protease mutations perturb the mechanistically crucial hinge axes that involve key sites for substrate binding and dimerization and mainly coordinate the intrinsic dynamics. Yet with substrate coevolution, while the wild-type dynamic behavior is restored in both p1-p6 (^LP1′Fp1-p6_D30N/N88D) and NC-p1 (^AP2VNC-p1_V82A) bound proteases, the dynamic behavior of the NC-p1 bound protease variants (NC-p1_V82A and ^AP2VNC-p1_V82A) rather resemble those of the proteases bound to the other substrates, which is consistent with experimental studies. The orientational variations of residue fluctuations along the hinge axes in mutant structures justify the existence of coevolution in p1-p6 and NC-p1 substrates, that is, the dynamic behavior of hinge residues should contribute to the interdependent nature of substrate recognition. Overall, this study aids in the understanding of the structural dynamics basis of drug resistance and evolutionary optimization in the HIV-1 protease system.

【 授权许可】

CC BY   
© 2014 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.