Coarse-Grained Modeling of the HIV-1 Protease Binding Mechanisms: I. Targeting Structural Flexibility of the Protease Flaps and Implications for Drug Design

摘要

We propose a coarse-grained model to study binding mechanism of the HIV-1 protease inhibitors using long equilibrium simulations with an ensemble of the HIV-1 protease crystal structures. A microscopic analysis suggests a binding mechanism, in which the HIV-1 protease drugs may exploit the dynamic equilibrium between thermodynamically stable, high affinity complexes with the closed form of the HIV-1 protease and meta-stable intermediate complexes with the alternative structural forms of the protease. We have found that formation of the hydrophobic interaction clusters with the conserved flap residues may stabilize semi-open and open forms of the enzyme and lead to weakly bound, transient inhibitor complexes. The results suggest that inhibitors may function through a multi-mechanistic effect of stabilizing structurally different conformational states of the protease, highlighting the molecular basis of the flap residues in developing drug resistance.