In order to elucidate the influences of V82A and L90M mutations on the HIV-1 protease (PR) and the indinavir (IDV) complex, molecular dynamics simulations have been successfully carried out for 5.5 nanoseconds. The binding free energies calculated by an MM-PBSA method are in agreement with the experimental ones. The analysis of the detailed interaction energies shows that the changes of entropic contribution in V82A and L90M complex are larger than changes of enthalpic contribution compared with the wild complex. Detailed binding free energies of the IDV and individual protein residue show that the wild, V82A and L90M complexes have a similar binding mode, and the binding free energies mainly come from six groups around A28/A28 , I50/I50 and I84/I84 . The mode between wild and IDV was analyzed in detail, the little changes of V82A were also compared with L90M. The changes of V82A mutation are caused by the steric hindrance, and those of L90M are by the stronger interaction between D25 and L90 compared with the wild. It was expected that this work could provide some helpful insights into the nature of mutational influences and aid design of better inhibitors in the future.

Key words: HIV-1 protease, mutation, molecular dynamics simulation