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Biophys. J. BioFAST: First Published December 8, 2006. doi:10.1529/biophysj.106.094409
© 2006 by the Biophysical Society.

A more recent version of this article appeared on March 1, 2007.
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BIOPHYSICAL THEORY AND MODELING

On the Characterization of Protein Native State Ensembles

Amarda Shehu 1, Lydia E Kavraki 1 and Cecilia Clementi 1*

1 Rice University

* To whom correspondence should be addressed. E-mail: cecilia{at}rice.edu.

Submitted on July 31, 2006
Revised on October 15, 2006
Accepted on 13 November 2006


  Abstract
Describing and understanding the biological function of a protein requires a detailed structural and thermodynamic description of the protein's native state ensemble. Obtaining such a description often involves characterizing equilibrium fluctuations that occur beyond the nanosecond timescale. Capturing such fluctuations remains non-trivial even for very long Molecular Dynamics and Monte Carlo simulations. We propose a novel multi-scale computational method to exhaustively characterize, in atomistic detail, the protein conformations constituting the native state with no inherent timescale limitations. Applications of this method to proteins of various folds and sizes show that thermodynamic observables measured as averages over the native state ensembles obtained by the method agree remarkably well with NMR data that span multiple timescales. By characterizing equilibrium fluctuations at atomistic detail over a broad range of timescales, from picoseconds to milliseconds, our method offers to complement current simulation techniques and wet-lab experiments and can impact our understanding and description of the relationship between protein flexibility and function.

Key Words: Native state ensemble, equilibrium fluctuations, order parameters, protein flexibility, scalar couplings




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Copyright © 2006 by the Biophysical Society.