Dynamical Network in HIV-1 Protease and its Mutants: Implications on Drug Resistance

Abstract

Drugs targeting HIV protease have long been used in AIDS therapy. However, emergence of multi-drug resistance, due to active and non-active site mutations, intensifies the need to understand the drug resistance mechanism of the enzyme. Here, we employ molecular dynamics (MD) simulations and network analyses to unravel the drug resistance mechanisms. Results from MD simulations suggest that the mutants modulate either the ligand binding envelop in the active site or the dynamics of flaps in HIV-1 protease. While the mutations at the active site or flap region account for drug resistance directly, the mechanism of allosteric mutations could not be explained. Network analyses show that the allosteric mutations affect the functional sites by modulating the stress centrality. Stress interference data ascribe the residues 71, 90 and 93 as the active site modulators and 15, 20 and 36 as the flap modulators. The integrity of the global network, however, was not affected by deletion of the mutant-prone nodes, indicating that the function of HIV-1 protease is preserved.