Molecular dynamics simulations of ligand-induced flap closing in HIV-1 protease approach X-ray resolution: establishing the role of bound water in the flap closing mechanism.

The necessity of understanding the detailed mechanism of flap dynamics in designing HIV-1 protease inhibitors is immense. Crystal structures have provided us with a static overview of various conformations of the enzyme, but the existence of strong interplay among various conformations came to the fore only after dynamics studies. Here we elucidate the mechanistic aspects of HIV-1 protease flap closing upon binding inhibitors using all-atom molecular dynamics simulations. The unrestrained simulations reproduced not only the correct inhibitor-bound protease closed structures but also the structural water molecule which is seen in all protease-ligand X-ray structures. The study demonstrates that the structural water plays a critical role in flap closing dynamics by destabilizing the hydrophobic clusters and subsequently by mediating the flap-ligand interactions. Our results corroborate well with prior simulation and experimental findings and, at the same time, provide a molecular level description of the HIV-1 protease flap closing mechanism which can be crucial in the understanding of drug-receptor interactions.