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Insights into amprenavir resistance in E35D HIV-1 protease mutation from molecular dynamics and binding free-energy calculations.

Abstract：

:Drug resistance is a very important factor contributing to the failure of current HIV therapies. The ability to understand the resistance mechanism of HIV-protease mutants may be useful in developing more effective and longer lasting treatment regimens. In this paper, we report the first computational study of the clinically relevant E35D mutation of HIV-1 protease in its unbound conformation and complexed with the clinical inhibitor amprenavir and a sample substrate (Thr-Ile-Met-Met-Gln-Arg). Our data, collected from 10 ns molecular-dynamics simulations, show that the E35D mutation results in an increased flexibility of the flaps, thereby affecting the conformational equilibrium between the closed and semi-open conformations of the free protease. The E35D mutation also causes a significant reduction of the calculated binding free energies both for substrate and amprenavir, thus giving a plausible explanation for its ability to increase the level of resistance. One possible explanation for the emergence of this mutation, despite its unfavorable effect on substrate affinity, might be the role of E35D as an escape mutation, which favors escape from the immune system in addition to conferring drug resistance.

journal_name

J Mol Model

journal_title

Journal of molecular modeling

authors

Meiselbach H,Horn AH,Harrer T,Sticht H

doi

10.1007/s00894-006-0121-3

subject

Has Abstract

pub_date

2007-02-01 00:00:00

pages

297-304

issue

2

eissn

1610-2940

issn

0948-5023

journal_volume

13

pub_type

杂志文章

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