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On the Characterization of Protein Native State Ensembles

Amarda Shehu ^*, Lydia E. Kavraki ^*   and Cecilia Clementi  

Departments of ^* Computer Science, Bioengineering, and Chemistry, Rice University, Houston, Texas; and Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas

Correspondence: Address reprint requests to Lydia E. Kavraki, Tel.: 713-348-5737; E-mail: kavraki{at}rice.edu; or address reprint requests to Cecilia Clementi, Tel.: 713-348-3485; E-mail: cecilia{at}rice.edu.

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 nontrivial even for very long molecular dynamics and Monte Carlo simulations. We propose a novel multiscale 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 nuclear magnetic resonance 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.

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