Decoding drug resistant mechanism of V32I, I50V and I84V mutations of HIV-1 protease on amprenavir binding by using molecular dynamics simulations and MM-GBSA calculations.

Mutations V32I, I50V and I84V in the HIV-1 protease (PR) induce drug resistance towards drug amprenavir (APV). Multiple short molecular dynamics (MSMD) simulations and molecular mechanics generalized Born surface area (MM-GBSA) method were utilized to investigate drug-resistant mechanism of V32I, I50V and I84V towards APV. Dynamic information arising from MSMD simulations suggest that V32I, I50V and I84V highly affect structural flexibility, motion modes and conformational behaviours of two flaps in the PR. Binding free energies calculated by MM-GBSA method suggest that the decrease in binding enthalpy and the increase in binding entropy induced by mutations V32I, I50V and I84V are responsible for drug resistance of the mutated PRs on APV. The energetic contributions of separate residues on binding of APV to the PR show that V32I, I50V and I84V highly disturb the interactions of two flaps with APV and mostly drive the decrease in binding ability of APV to the PR. Thus, the conformational changes of two flaps in the PR caused by V32I, I50V and I84V play key roles in drug resistance of three mutated PR towards APV. This study can provide useful dynamics information for the design of potent inhibitors relieving drug resistance.