Molecular Dynamic and Free Energy Studies of Primary Resistance Mutations in HIV-1 Protease−Ritonavir Complexes

Abstract

To understand the basis of drug resistance of the HIV-1 protease, molecular dynamic (MD) and free energy calculations of the wild-type and three primary resistance mutants, V82F, I84V, and V82F/I84V, of HIV-1 protease complexed with ritonavir were carried out. Analysis of the MD trajectories revealed overall structures of the protein and the hydrogen bonding of the catalytic residues to ritonavir were similar in all four complexes. Substantial differences were also found near the catalytic binding domain, of which the double mutant complex has the greatest impact on conformational changes of the protein and the inhibitor. The tip of the HIV-1 protease flap of the double mutant has the greater degree of opening with respect to that of the others. Additionally, the phenyl ring of Phe82 moves away from the binding pocket S1', and the conformational change of ritonavir subsite P1' consequently affects the cavity size of the protein and the conformational energy of the inhibitor. Calculations of binding free energy using the solvent continuum model were able to reproduce the same trend of the experimental inhibition constant. The results show that the resistance mutants require hydrophobic residues to maintain the interactions in the binding pocket. Changes of the cavity volume correlate well with free energy penalties due to the mutation and are responsible for the loss of drug susceptibility.