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Biophys. J. BioFAST: First Published March 13, 2006. doi:10.1529/biophysj.105.074575
© 2006 by the Biophysical Society.

A more recent version of this article appeared on June 1, 2006.
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BIOPHYSICAL THEORY AND MODELING

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

Chia-en Chang 1*, Tongye Shen 1, Joanna Trylska 2, Valentina Tozzini 3 and J. Andrew McCammon 4

1 University of California, San Diego
2 Warsaw University, Warsaw, Poland
3 NEST Scuola Normale Superiore, Italy
4 University of California - San Diego

* To whom correspondence should be addressed. E-mail: cchang{at}mccammon.ucsd.edu.

Submitted on October 25, 2005
Revised on December 12, 2005
Accepted on 27 January 2006


  Abstract
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 two protease mutants, G48V/V82A/I84V/L90M 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 and the L90M mutant 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 for various protease mutants and ligands.

Key Words: association rate constants, diffusional control, gating effects, protein dynamics, protein internal motions, protein-ligand binding




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Copyright © 2006 by the Biophysical Society.