The long-term goals of this proposal are to uncover the fundamental mechanisms of protein folding and/or misfolding, and, eventually, to predict protein structures from sequences using bioinformatic, theoretical, and computational methods. This proposal addresses the challenge of developing a computational model that is detailed enough to capture the specific folding behavior of a given protein, but is simple enough to permit efficient calculations. We propose to develop an all-atom model based on simplified potentials. Preliminary studies show that this new all-atom model allows practical folding simulations using regular PCs, and that it yields unprecedented accuracy in predicting the folding pathway(s) of a given protein. This initial success and productivity provide strong incentives for the further development and validation of this method. The new model will be used to examine the extent to which the tertiary structure encodes the varieties of folding mechanisms and the effect of non-native hydrogen bonding and nonnative hydrophobic interactions. In this regard, various all-atom models of the Pin WW domain will be tested. Results will be compared against available experimental data. The knowledge gained from the proposed studies will, not only advance our understanding of how specific proteins fold, but also should be useful for designing mutants that are optimized for folding and stability. The analytic tools and computational methods developed in the proposal have the potential to be widely used by those who are interested in determining the preferred folding pathways.
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