Understanding The Mechanism of Mutant HIV-1 Protease Resistance Against Darunavir Using Molecular Dynamic Study

Abstract The human immunodeficiency virus type 1 protease (HIV-1 PR) is an important enzyme in life cycle of the HIV virus. It cleaves inactive pre-proteins of the virus and changes them into active proteins. Darunavir suppresses the wild type HIV-1 PR (WT-Pr) activity, but can’t inhibit the mutant resistant forms (MUT-Pr). Increasing knowledge about the resistance mechanism can be helpful for designing of more effective inhibitors. In this study, the mechanism of resistance of Ile47val and Ile54Met MUT-Pr strain against Darunavir was investigated. For this purpose, complexes of Darunavir with WT-Pr (WT-Pr-D) and MUT-Pr (MUT-Pr-D) were simulated for 200 ns and structure, dynamic and energetic properties of both simulations were investigated based on essential dynamics (principal component analysis (PCA)), root mean square fluctuation (RMSF), radial distribution function (RDF), molecular mechanics/Poisson Boltzman surface area (MM/PBSA) energies and etc. Our data revealed that mutations increased the flap tips flexibility and increased the active-site space, probably due to the reduction in hydrophobic forces. So, the protease’s conformation changed from closed state to semi-open state. Formation of semi open structure along with a reduction in van der Waals interactions and hydrogen bonds with Darunavir facilitates disjunction of Darunavir from the active-site in MUT-Pr-D.