Binding of single walled carbon nanotube to WT and mutant HIV-1 proteases: Analysis of flap dynamics and binding mechanism

Most of the currently treated HIV-1 protease (HIV-PR) inhibitors have been prone to suffer from the mutations associated drug resistance. Therefore, it is necessary to search for potent alternatives against the drug resistance. In the current study we have tested the single-walled carbon nanotube (SWCNT) as an inhibitor in wild type (WT) as well as in three primary mutants (I50VPR, V82APR and I84VPR) of the HIV-1-PR through docking the SWCNT in the active site region, and then performed all-atom MD simulations for the complexes. The conformational dynamics of HIV-PR with a 20 ns trajectory reveals that the SWCNT can effectively bind to the HIV-1-PR active site and regulate the flap dynamics such as maintaining the flap-flap closed. To gain an insight into the binding affinity, we also performed the MM-PBSA based binding free energy calculations for the four HIV-PR/SWCNT complexes. It was observed that, although the binding between the SWCNT and the HIV-PR decreases due to the mutations, the SWCNTs bind to the HIV-PRs 3–5 folds stronger than the most potent HIV-1-PR inhibitor, TMC114. Remarkably, the significant interactions with binding energy higher than 1 kcal/mol focus on the flap and active regions, which favors closing flap-flap and deactivating the active residues of the HIV-PR. The flap dynamics and binding strength information for HIV-PR and SWCNTs can help design SWCNT-based HIV-1-PR inhibitors.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (286 K)Download as PowerPoint slideHighlights► The flap dynamics and binding energetic for the HIV-I mutants with SWCNT were reported in the manuscript for the first time. ► The report reveals that in spite of binding strength decrease due to the investigated mutants the bindings are still rather significant, keeping flap-flap close and deactivating the active residues. ► The significant interactions with binding energy higher than 1 kcal/mol focus on flap and active regions, and detailed mechanism were provided. ► The flap dynamics and binding strength information for HIV-PR and SWCNTs can help design SWCNT-based HIV-PR inhibitors.