Full elucidation of the mechanisms of protein folding and misfolding requires detailed knowledge of the molecular events leading to the formation of both native and non-native states. 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 an all-atom representation of both protein and solvent. 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 proteins and peptides. This proposal will incrementally address three key areas. Simulations on two topologically simple proteins, including FSD1 (a beta/beta/alpha module) and protein A (a three-helix bundle), will allow us to study tertiary structure formation and its dependence on the secondary structures. Insights on the role of hydrophobic interactions are also expected to emerge. Tertiary and secondary structure formation will be examined further by simulations of two topologically challenging proteins, including protein G (an alpha/beta protein) and monomeric lambda repressor (an alpha-helical protein). Multiple hydrophobic clusters may form during folding of these two proteins. It is therefore interesting to see how they coalesce and how they repack. We will develop methods for accurate protein folding simulation and protein structure prediction. We will focus on initiation, hydrophobic core, tertiary structure formation and its dependence on the secondary structures. 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 on the approach.
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