Investigating the flap dynamics of HIV‐1 Protease

Abstract

The potency of the HIV virus arises from the unknowing spread of the disease. Within the United States, it is estimated that one in four people newly infected with HIV is between the ages of thirteen and twenty‐four. (1) The HIV protease is an essential enzyme that cleaves three previral polyproteins leading to the maturation of the virus. The HIV virus mutates at a rapid pace, resulting in the emergence of HIV resistance to protease inhibitors. In 2003, it was suggested by Wu et al. that the flap tips of the HIV protease control enzyme activity. (2) Although the HIV‐1 protease flap dynamics have been studied extensively using both experimental and computational methods, rarely have all four flap tip conformations been observed in a single computer simulation. In addition, it has been suggested that one of the observed conformations was an artifact of crystal packing forces. (3) By performing long‐time scale simulations with two different force fields (CHARMM27 and AMBERff99SB) we were able to observe the existence of all four conformational states: closed, semi‐open, open, and wide‐open states. The lifetimes and percent occupancies of the conformations were determined through energy and structural analyses. Further analyses were performed to quantify stability and sampling of all simulations. These results will be presented and comparisons made with experimental results.(1) AIDS.gov 2013.(2) Wu, T. D.; Schiffer, C. A.; Gonzales, M. J.; Taylor, J.; Kantor, R.; Chou, S.; Israelski, D.; Zolopa, A. R.; Fessel, W. J.; Shafer, R. W. J Virol 2003, 77, 4836.(3) Layten, M.; Hornak, V.; Simmerling, C. J. Am. Chem. Soc. 2006, 128, 13360.