Understanding the Structural and Functional Effects of Mutations in HIV-1 Protease Mutants Using 100ns Molecular Dynamics Simulations

Abstract

The Human Immunodeficiency Virus type 1 protease (HIV-1 PR) performs a vital role in the lifecycle of the virus, specifi-cally in the maturation of new viral particles. Therefore, de-laying the onset of AIDS, the primary goal of HIV treatment, can be achieved by inhibiting this protease[2]. However, the rapidly mutating virus quickly develops drug resistance to current inhibitors, thus novel protease inhibitors are needed. Here, 100ns molecular dynamics (MD) simulations were con-ducted for the wild type and two mutant proteases to gain insight into the mechanisms by which the mutations con-fer drug resistance. Several different metrics were used to search for differences between the wild type and mutant pro-teases including: flap tip distance and root-mean-square de-viation (RMSD), mutual information, and Kullback-Leibler divergence. It was found that at the 100ns timescale there were no large differences in the structure, flexibility and motions of the wild type protease relative to the mutants, and longer simulations may be needed to identify how the structural changes imparted by the mutations affect the pro-tease's functionality.