The structural, dynamic, and thermodynamic basis of darunavir resistance of a heavily mutated HIV-1 protease using molecular dynamics simulation

Yaser Shabanpour; Sharareh Sajjadi; Esmaeil Behmard; Parviz Abdolmaleki; Amir Homayoun Keihan

doi:10.3389/fmolb.2022.927373

The structural, dynamic, and thermodynamic basis of darunavir resistance of a heavily mutated HIV-1 protease using molecular dynamics simulation

Front Mol Biosci. 2022 Aug 15:9:927373. doi: 10.3389/fmolb.2022.927373. eCollection 2022.

Authors

Yaser Shabanpour¹, Sharareh Sajjadi², Esmaeil Behmard³, Parviz Abdolmaleki⁴, Amir Homayoun Keihan¹

Affiliations

¹ Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
² Department of Biology, Roudehen Branch, Islamic Azad University, Roudehen, Iran.
³ Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
⁴ Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.

Abstract

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.

Keywords: HIV-1 protease; PCA analysis; darunavir; drug resistance; molecular dynamics simulation.