CAREER: Bridging "In Vitro" and "In Vivo" Protein Folding: An Integrated Interdisciplinary Research and Teaching Plan

University Of California-Santa Barbara, Santa Barbara CA

Investigators

Abstract

The current understanding of the mechanism by which a protein folds and adopts its biologically active three dimensional structure stems from experimental and theoretical investigations in idealized dilute environments. Under biologically relevant conditions, however, proteins fold in the much more complex cellular environment, where folding is plagued by a number of obstacles. For example, the crowded cytoplasmic environment, sequence mutations and changes in pH or temperature, can all lead to the formation of misfolded or intermediate structures. While recent experimental advances are permitting an exploration of folding in the cell, a theoretical framework and understanding of protein folding in the cellular environment is lacking. This project seeks to bridge the gap in our theoretical knowledge between in vitro and in vivo protein folding. Methods of statistical physics will be used to develop new methods and models to further our understanding of protein folding and to develop a microscopic picture of the kinetics and thermodynamics of protein aggregation. New algorithms based on parallel tempering Molecular Dynamics, Stationary Phase Monte Carlo and Field Theoretic methods will be developed to efficiently sample relevant aggregate conformations. The effect of crowding on folding and the competition between folding, misfolding and aggregation will be addressed. The educational goals of this project relate to the interdisciplinary nature of this research. A reform of the chemistry curriculum, to reflect the growing interdisciplinary nature of biochemical research and the impact of computers in modern research, will be achieved through the development of a new computational biophysics and chemistry course as well as through the creation of an interdisciplinary undergraduate research program. Outreach activities will be pursued through introductory computer classes aimed at middle school girls.