Rigidity analysis of HIV-1 protease

TL;DR

This study applies rigidity analysis to numerous HIV-1 protease structures, revealing how inhibitors restrict enzyme flexibility, especially in the active site access regions, with implications for drug design.

Contribution

The paper introduces a comprehensive rigidity analysis of HIV-1 protease structures, highlighting the impact of inhibitors on enzyme flexibility using the pebble game algorithm.

Findings

Rigidity profiles are consistent across high-resolution structures.

Inhibitors significantly reduce flexibility of the beta-hairpin flaps.

Rigidity analysis correlates with molecular dynamics and NMR data.

Abstract

We present a rigidity analysis on a large number of X-ray crystal structures of the enzyme HIV-1 protease using the 'pebble game' algorithm of the software FIRST. We find that although the rigidity profile remains similar across a comprehensive set of high resolution structures, the profile changes significantly in the presence of an inhibitor. Our study shows that the action of the inhibitors is to restrict the flexibility of the beta-hairpin flaps which allow access to the active site. The results are discussed in the context of full molecular dynamics simulations as well as data from NMR experiments.