Understanding the basis of G140S-Q148H double mutation induced drug resistance in HIV-1 integrase using molecular dynamics simulation

Abstract

On the basis of the accurate calculation of binding free energy variation caused by G140S-Q148H double mutation in HIV-1 integrase, different effects of the mutation on raltegravir (RAL) and dolutegravir (DTG) were explored by molecular dynamics simulation. The simulation results show that the formation of a hydrogen bond between S140 and H148 upon the mutation and the interaction between the terminal oxadiazol group in RAL and Y143 in the middle of the 140′s loop together cause the loop to be pushed outward, leading to a significant reduction of the binding free energy of RAL with the double mutant.