Coarse-Grained Modeling of the HIV–1 Protease Binding Mechanisms: II. Folding Inhibition
Evolutionary and structurally conserved fragments 24–34 and 83–93 from each of the HIV–1 protease (HIV–1 PR) monomers constitute the critical components of the HIV–1 PR folding nucleus. It has been recently discovered that the peptide with the amino acid sequence NIIGRNLLTQI identical to the corresponding segment 83–93 of the HIV–1 PR monomer, can inhibit folding of HIV–1 PR. We have previously shown that this peptide can form stable complexes with the folded HIV–1 PR monomer by targeting the conserved segment 24–34 of the folding nucleus (folding inhibition) and by interacting with the antiparallel termini β–sheet region (dimerization inhibition). In this follow-up study, we propose a generalized, coarse–grained model of the folding inhibition based simulations with an ensemble of both folded and partially unfolded HIV–1 PR conformational states. Using a dynamic equilibrium between low–energy complexes formed with the folded and partially unfolded HIV–1 PR monomers, the NIIGRNLLTQI peptide may effectively intervene with the HIV–1 PR folding and dimerization. The performed microscopic analysis reconciles the experimental and computational results and rationalizes the molecular basis of folding inhibition.
KeywordsHIV–1 protease folding inhibitors protein conformational ensembles molecular docking Monte Carlo simulations drug design
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