Abstract
BackgroundProtease inhibitors designed to bind to protease have become major anti-AIDS drugs. Unfortunately, the emergence of viral mutations severely limits the long-term efficiency of the inhibitors. The resistance mechanism of these diversely located mutations remains unclear.ResultsHere I use an elastic network model to probe the connection between the global dynamics of HIV-1 protease and the structural distribution of drug-resistance mutations. The models for study are the crystal structures of unbounded and bound (with the substrate and nine FDA approved inhibitors) forms of HIV-1 protease. Coarse-grained modeling uncovers two groups that couple either with the active site or the flap. These two groups constitute a majority of the drug-resistance residues. In addition, the significance of residues is found to be correlated with their dynamical changes in binding and the results agree well with the complete mutagenesis experiment of HIV-1 protease.ConclusionsThe dynamic study of HIV-1 protease elucidates the functional importance of common drug-resistance mutations and suggests a unifying mechanism for drug-resistance residues based on their dynamical properties. The results support the robustness of the elastic network model as a potential predictive tool for drug resistance.
Highlights
Protease inhibitors designed to bind to protease have become major anti-AIDS drugs
Here HIV-1 protease is represented by a coarse-grained network model, and its dynamics is examined in several X-ray crystallographic structures
The linkage between global dynamics and the distribution of drug-resistance mutations is examined first in individual unbound and bound forms, in the dynamical differences between the unbound and bound forms. The former is a measure of the residual fluctuations in different structures, and the latter is an estimate of dynamical change caused by ligand binding
Summary
Protease inhibitors designed to bind to protease have become major anti-AIDS drugs. the emergence of viral mutations severely limits the long-term efficiency of the inhibitors. HIV-1 protease (human immunodeficiency virus type 1 protease) is an enzyme that plays a critical role in the virus replication cycle. It cleaves the gag and pol viral polyproteins at the active site to process viral maturation [1,2,3], and without HIV-1 protease the virus was found to be noninfectious [4]. Variants are able to evolve resistance by developing a chain of mutations, and as a result limit the long-term efficiency of these drugs [7,8]. The enzyme active site is a catalytic triad composed of Asp25-Thr26-Gly from each monomer. It is gated by two extended b hairpin loops (residues 46−56) known as flaps [9]. Mutations associated with drug resistance occur within the active site as well as non-active distal sites [11]
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