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Science 21 July 1995:
Vol. 269. no. 5222, pp. 393 - 396
DOI: 10.1126/science.7618103
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Articles

Science, Vol 269, Issue 5222, 393-396
Copyright © 1995 by American Association for the Advancement of Science

articles

First-principles calculation of the folding free energy of a three-helix bundle protein

EM Boczko and CL Brooks 3rd

Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.

The folding and unfolding of a three-helix bundle protein were explored with molecular-dynamics simulations, cluster analysis, and weighted-histogram techniques. The folding-unfolding process occurs by means of a "folding funnel," in which a uniform and broad distribution of conformational states is accessible outside of the native manifold. This distribution narrows near a transition region and becomes compact within the native manifold. Key thermodynamic steps in folding include initial interactions around the amino-terminal helix-turn-helix motif, interactions between helices I and II, and, finally, the docking of helix III onto the helix I-II subdomain. A metastable minimum in the calculated free-energy surface is observed at approximately 1.5 times the native volume. Folding-unfolding thermodynamics are dominated by the opposing influences of protein-solvent energy, which favors unfolding, and the overall entropy, which favors folding by means of the hydrophobic effect.


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