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Gated Binding of Ligands to HIV-1 Protease: Brownian Dynamics Simulations in a Coarse-Grained Model

Chia-En Chang ^* , Tongye Shen , Joanna Trylska , Valentina Tozzini  and J. Andrew McCammon ^*  ¶ ||

^* Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, ^¶ Howard Hughes Medical Institute, and ^|| Department of Pharmacology, University of California at San Diego, La Jolla, California; Interdisciplinary Centre for Mathematical and Computational Modelling, Warsaw University, Warsaw, Poland; and NEST Scuola Normale Superiore, Piazza dei Cavalieri, Pisa, Italy

Correspondence: Address reprint requests to Chia-En Chang, E-mail: cchang{at}mccammon.ucsd.edu.

The internal motions of proteins may serve as a "gate" in some systems, which controls ligand-protein association. This study applies Brownian dynamics simulations in a coarse-grained model to study the gated association rate constants of HIV-1 proteases and drugs. The computed gated association rate constants of three protease mutants, G48V/V82A/I84V/L90M, G48V, and L90M with three drugs, amprenavir, indinavir, and saquinavir, yield good agreements with experiments. The work shows that the flap dynamics leads to "slow gating". The simulations suggest that the flap flexibility and the opening frequency of the wild-type, the G48V and L90M mutants are similar, but the flaps of the variant G48V/V82A/I84V/L90M open less frequently, resulting in a lower gated rate constant. The developed methodology is fast and provides an efficient way to predict the gated association rate constants for various protease mutants and ligands.

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