help button home button Biophys. J.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Biophys. J. BioFAST: First Published March 23, 2007. doi:10.1529/biophysj.106.100560
© 2007 by the Biophysical Society.

A more recent version of this article appeared on June 15, 2007.
This Article
Right arrow Full Text (Rapid PDF)
Right arrow Supplement
Right arrow All Versions of this Article:
biophysj.106.100560v1
92/12/4179    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Author home page(s):
Joanna Trylska
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Trylska, J.
Right arrow Articles by McCammon, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Trylska, J.
Right arrow Articles by McCammon, J. A.

BIOPHYSICAL THEORY AND MODELING

HIV-1 protease substrate binding and product release pathways explored with coarse-grained molecular dynamics

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

1 ICM Warsaw University
2 NEST CNR-INFM Scuola Normale Superiore
3 University of California, San Diego
4 University of California - San Diego

* To whom correspondence should be addressed. E-mail: joanna{at}icm.edu.pl.

Submitted on November 7, 2006
Revised on December 18, 2006
Accepted on 18 January 2007


  Abstract
We analyse the encounter of a polypeptide substrate with the native HIV-1 protease, the mechanism of substrate incorporation in the binding cleft, and the dissociation of products after substrate hydrolysis. To account for the substrate, we extend a coarse-grained model force field which we previously developed to study the flap opening dynamics of HIV-1 protease on a microsecond time scale. Molecular and Langevin dynamics simulations show that the flaps need to open for the polypeptide to bind and that the protease interaction with the substrate influences the flap opening frequency and interval. On the other hand, release of the products does not require flap opening because they can slide out from the binding cleft to the sides of the enzyme. Our data show that in the protease-substrate complex the highest fluctuations correspond to the 17- and 39-turns and the substrate motion is anti-correlated with the 39-turn. Moreover, the active site residues and the flap tips move in phase with the polypeptide. We suggest some mechanistic principles for how the flexibility of the protein may be involved in ligand binding and release.

Key Words: HIV-1 protease, coarse-grained models, molecular dynamics, substrate binding and cleavage




This article has been cited by other articles:


Home page
 Biophys. JHome page
G. Verkhivker, G. Tiana, C. Camilloni, D. Provasi, and R. A. Broglia
Atomistic Simulations of the HIV-1 Protease Folding Inhibition
Biophys. J., July 15, 2008; 95(2): 550 - 562.
[Abstract] [Full Text] [PDF]

Home page
 Biophys. JHome page
A. A. Gorfe, C.-e. A. Chang, I. Ivanov, and J. A. McCammon
Dynamics of the Acetylcholinesterase Tetramer
Biophys. J., February 15, 2008; 94(4): 1144 - 1154.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Copyright © 2007 by the Biophysical Society.