Insights into drug resistance of mutations D30N and I50V to HIV-1 protease inhibitor TMC-114: free energy calculation and molecular dynamic simulation.

The single mutations D30N and I50V are considered as the key residue mutations of the HIV-1 protease drug resistance to inhibitors in clinical use. In this work, molecular dynamics (MD) simulations combined with the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method have been performed to investigate the drug-resistant mechanisms of D30N and I50V to an inhibitor TMC-114. The analyses of absolute binding free energies using the separate trajectory approach suggests that the decrease in the van der Waals energy and electrostatic energy in the gas phase results in the drug resistance of D30N to TMC-114, while for I50V, the decrease in the electrostatic energy mainly drive its drug resistance to TMC-114. Detailed binding free energies between TMC-114 and individual protein residues are computed by using a per-residue basis decomposition method, which provides insights into the inhibitor-protein binding mechanism and also explains the drug-resistant mechanisms of mutations D30N and I50V to TMC-114. The study shows that the loss of the hydrogen bond between TMC-114 and the side chain of Asn30' is the main driving force of the resistance of D30N to TMC-114, and in the case of I50V, the increase in the polar solvation energies between TMC-114 and two residues Val50' and Asp30' definitively drives the resistance of I50V to TMC-114. We expect that this work can provide some helpful insights into the nature of mutational effect and aid the future design of better inhibitors.