Investigating potency of TMC-126 against wild-type and mutant variants of HIV-1 protease: a molecular dynamics and free energy study.

A detailed computational study was performed to investigate the conformational changes of flap region and the mechanism underlying the binding of the inhibitor TMC-126 to HIV-1 protease (PR1) and its mutant variants through molecular dynamics simulations in conjunction with the molecular mechanics Poisson-Boltzmann (MM-PBSA) free energy calculation. Further, we have studied the effectiveness of the inhibitor against HIV-2 protease (PR2). The MM-PBSA calculation suggests that TMC-126 loses its potency against mutant variants and PR2 compared to wild-type PR1 mainly due to the loss in intermolecular electrostatic interactions. The potency of the inhibitor decreases in the order: wild type PR1 > M46L > MDR20 > I50V > PR2 > V32I > A28S. Our study reveals that the flap of PR1 adopts a semi-open conformation due to the mutation I50V or MDR20. The dissimilar nature of the movement of the flap tip of both monomers is evident from the dynamic cross-correlation map. The protein structural network analysis displays that mutation causes structural rearrangements and changes the communication path between residues. Overall, we believe our study may help explore and accelerate the development of novel HIV-1/HIV-2 protease inhibitors with better potency.