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1 Biomolecular Structure and Design Program and 2 Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195-7610, USA
(RECEIVED November 9, 2004; FINAL REVISION February 9, 2005; ACCEPTED February 9, 2005)
To better characterize the transition state for folding/unfolding and its sensitivity to environmental changes, we have run multiple molecular dynamics simulations of chymotrypsin inhibitor 2 (CI2) under varying solvent conditions and temperature. The transition state structures agree well with experiment, and are similar under all of the conditions investigated here. Increasing the temperature leads to some movement in the position of the transition state along several reaction coordinates, as measured by changes in properties of the transition state structures. These structural changes are in the direction of a more native-like transition state as denaturation conditions become more severe, as expected for a Hammond effect. These structural changes are not, however, reflected in the global structure as measured by the total number of contacts or the average S-values. These results suggest that the small changes in average 
-values with temperature seen by experiment may be due to an increase in the sensitivity of the transition state to mutation rather than a change in the average structure of the transition state. A simple analysis of the rates of unfolding indicates that the free energy barrier to unfolding decreases with increasing temperature, but even in our very high temperature simulations there is a small free energy barrier.
Keywords: transition state; Hammond effect; molecular dynamics; chymotrypsin inhibitor 2; unfolding rate
Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041226005.
Reprint requests to: Valerie Daggett, Department of Medicinal Chemistry, University of Washington, Box 357610, Seattle, WA 98195-7610, USA; e-mail: daggett{at}u.washington.edu.
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