The human immunodeficiency virus type 1 protease (HIV-1 PR) is an important enzyme in the life cycle of the HIV virus. It cleaves inactive pre-proteins of the virus and changes them into active proteins. Darunavir (DRV) suppresses the wild-type HIV-1 PR (WT-Pr) activity but cannot inhibit some mutant resistant forms (MUT-Pr). Increasing knowledge about the resistance mechanism can be helpful for designing more effective inhibitors. In this study, the mechanism of resistance of a highly MUT-Pr strain against DRV was investigated. For this purpose, complexes of DRV with WT-Pr (WT-Pr-D) and MUT-Pr (MUT-Pr-D) were studied by all-atom molecular dynamics simulation in order to extract the dynamic and energetic properties. Our data revealed that mutations increased the flap-tip flexibility due to the reduction of the flap-flap hydrophobic interactions. So, the protease’s conformation changed from a closed state to a semi-open state that can facilitate the disjunction of DRV from the active site. On the other hand, energy analysis limited to the final basins of the energy landscape indicated that the entropy of binding of DRV to MUT-Pr was more favorable than that of WT-Pr. However, the enthalpy penalty overcomes it and makes binding more unfavorable relative to the WT-Pr. The unfavorable interaction of DRV with R8, I50, I84, D25′, and A28′ residues in MUT-Pr-D relative to WT-Pr-D is the reason for this enthalpy penalty. Thus, mutations drive resistance to DRV. The hydrogen bond analysis showed that compared with WT-Pr, the hydrogen bonds between DRV and the active-site residues of MUT-Pr were disrupted.

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.