CAREER: Understanding Protein Folding Dynamics in the Ultra-Fast Limit

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This project will investigate some of the unique phenomena associated with protein folding and assembly on very fast time scales. Nanosecond and microsecond events in protein folding can now be probed by experimentalists using laser spectroscopy, and by theorists using state-of-the-art molecular dynamics simulation. Because many small, newly-designed proteins and peptides fold rapidly, ultra-fast folding is the regime where the experimental, theoretical, and design aspects of protein folding all converge. However, it is also a regime that strains the assumptions and interpretations behind standard physical descriptions of the protein folding problem: fast folding is different from slow folding. This project applies time-resolved laser spectroscopy to small, designed proteins and peptides in order to examine the limits of standard barrier-crossing descriptions of folding, and to investigate how the assumptions behind those descriptions may break down for the very fastest folding molecules. It focuses on (1) the meaning of reaction friction in Kramers models for folding, (2) the speed of rapid reorganizations of unfolded polypeptides, and (3) the deviation from simple barrier-crossing kinetics that is expected for ultrafast folding.The broader impact of this project derives in part from its advancement of basic understanding of the limits of simple physical models for complex biochemical phenomena, and from the fact that it supports time-resolved spectroscopic instrumentation that enhances the scientific research infrastructure in molecular biophysics. A broader impact also derives the educational components of the plan. The PI will lead a K-12 outreach effort aimed at a local middle school that has a large minority enrollment and substantial numbers of disadvantaged students. The project aims to motivate and support the participation of more of these students in the optional science fair by providing them with regular mentoring over a period of many weeks as they undertake their science fair projects. The plan also provides for research laboratory teaching and training for undergraduate and graduate students in interdisciplinary biological physics: This training initiates physical-science students into the study of biological systems, and it introduces biologically-inclined students to physical instrumentation and methodologies. This project is jointly funded by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences and the Division of Physics in the Mathematical and Physical Sciences Directorate.