MECHANISM OF FOLDING OF THE SH3 DOMAIN

University Of Washington, Seattle WA

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Abstract

The objective of this proposal is to use a combination of experimental and computational approaches to develop a physically plausible model for the folding of the src SH3 domain capable of accurately predicting the results of further experimental measurements. The rate limiting step in folding will be probed by analyzing the kinetic consequences of both single and multiple amino acid substitutions in combination with both all atom and simplified computational models. The starting point of the folding reaction, the denatured state, will be probed by studying peptide models, the kinetics of exchange from the native state, and by direct NMR characterization. The importance of hydrophobic-hydrophyllic patterning and the relationship between sequence conservation and kinetics will be investigated using phage display selection methods. The experimental data will be compared with the results of computational methods including a recently developed ab initio folding simulation method, a simple model which computes the rate and transition state structure from the sequence and native state using simple physical principles, and all atom MD simulations. The ultimate goal is a therapy for beta sheet proteins capable for predicting the folding rate, the structure in the transition state ensemble, and the residual structure in the denatured state from the sequence and structure of the native protein.