Protein folding has been referred to as the second half of genetics. A detailed knowledge about the stability and folding mechanisms of small peptides that can form stable secondary structures is an important step toward a full elucidation of the mechanisms of protein folding and misfolding. Recent advances, which this investigator has helped to develop, have made it possible to study microsecond time-scale molecular events leading to the formation of a native-like state of a small protein with all-atom representation of both protein and solvent. To further advance our understanding, we will apply all-atom molecular dynamics simulations, with both explicit and continuum solvent models, to characterize the non-native states that are relevant to the folding and misfolding of small peptides. This proposal will incrementally address four key areas: 1) Simulations on helical peptides, including alanine-based peptides (AK16, AQ16, and Fs-peptides), will be used to study helical secondary structure formation. The rate-limiting steps in helix formation will be investigated. 2) a beta-hairpin formation will be studied to obtain information on the molecular events leading to the initiation, the physical interactions determining the rate-limiting steps, and the folding pathways. These studies will allow us to examine the balance of our approach in the important alpha-helical and beta-sheet conformations. 3) Tertiary contacts and their role in secondary structure formation will be studied using the C-terminal helix-hairpin (helices II and III) of the B domain of Staphylococcal protein A and the three-stranded anti-parallel beta-sheet peptides as model systems. These studies will allow a rigorous evaluation on the accuracy of our approach in modeling the tertiary contacts. Comparison with experiments, including direct tests on the predictive ability of our model will be an integral part of our study and will be instrumental for a close scrutiny of the approach. 4) Continuum solvent models will be developed for molecular dynamics simulations.
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