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Published online before print March 9, 2004
Protein Science, DOI: 10.1110/ps.03449904
 Copyright © 2004 The Protein Society
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Mimicking the action of folding chaperones in molecular dynamics simulations: Application to the refinement of homology-based protein structures

Hao Fan and Alan E. Mark

Groningen Biomolecular Sciences and Biotechnology Institute (GBB), Department of Biophysical Chemistry, University of Groningen, 9747 AG Groningen, The Netherlands

(RECEIVED September 19, 2003; FINAL REVISION November 26, 2003; ACCEPTED November 26, 2003)



Abstract

A novel method for the refinement of misfolded protein structures is proposed in which the properties of the solvent environment are oscillated in order to mimic some aspects of the role of molecular chaperones play in protein folding in vivo. Specifically, the hydrophobicity of the solvent is cycled by repetitively altering the partial charges on solvent molecules (water) during a molecular dynamics simulation. During periods when the hydrophobicity of the solvent is increased, intramolecular hydrogen bonding and secondary structure formation are promoted. During periods of increased solvent polarity, poorly packed regions of secondary structures are destabilized, promoting structural rearrangement. By cycling between these two extremes, the aim is to minimize the formation of long-lived intermediates. The approach has been applied to the refinement of structural models of three proteins generated by using the ROSETTA procedure for ab initio structure prediction. A significant improvement in the deviation of the model structures from the corresponding experimental structures was observed. Although preliminary, the results indicate computationally mimicking some functions of molecular chaperones in molecular dynamics simulations can promote the correct formation of secondary structure and thus be of general use in protein folding simulations and in the refinement of structural models of small- to medium-size proteins.

Keywords: protein structure prediction; homology modeling; molecular dynamics; structure refinement; chaperone

Reprint requests to: Alan E. Mark, Groningen Biomolecular Sciences and Biotechnology Institute, Department of Biophysical Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands; e-mail: mark{at}chem.rug.nl; fax: 31-50-3634800.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03449904.


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