Multiple Molecular Dynamics Simulations and Free-Energy Predictions Uncover the Susceptibility of Variants of HIV-1 Protease against Inhibitors Darunavir and KNI-1657.

HIV-1 protease (PR) is considered to be the main targets of anti-AIDS drug design because of its role in the proteolytic processing of viral polyproteins. However, the emergence of drug-resistant HIV has become a major problem in the therapy of HIV-1-infected patients. Focused on the complexes of wild type (WT) PR and two mutant PRs (V32I/L33F/I54M/V82I and V32I/L33F/I54M/I84 V) with inhibitors Darunavir (DRV) and KNI-1657 (KNI), respectively, we have conducted research on the conformational dynamics and the resistance mechanism caused by residue mutations through multiple molecular dynamics (MD) simulations combined with an energy (MM-PBSA and solvated interaction energy (SIE)) prediction. The results indicate that mutated residues of PR alter the distance between flap regions and catalytic sites, the volume of the inner catalytic site, and the curling degree of the flap tips, thereby affecting DRV and KNI inhibitor binding to PR. These mutated residues reduced the binding affinity of the two mutant PRs to DRV, resulting in drug resistance, whereas the two mutant PRs increase the binding affinity with KNI, indicating they enhance the sensitivity to KNI. Compared with the WT PR, the changes in van der Waals interaction and electrostatic interaction in the two variant PRs play a vital part in the binding of PR with DRV and KNI. These results may supply valuable guidance for the design of anti-AIDS drugs targeting PR.