Coarse-grained modeling of the HIV-1 protease binding mechanisms: II. Folding inhibition

Abstract

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. © 2009 Springer Berlin Heidelberg.