The objective of this project is to investigate the protein-folding problem using single molecule studies. Protein folding, the mechanism by which the amino acid sequence directs the energy landscape of a protein (the structures, energies, and rates of interconversion of all of the accessible conformations), remains a major challenge for modern molecular biology. Without a better understanding of how these features are encoded in a protein sequence, the expanding sequence databases continue to conceal the answers to many important questions. The project aims to develop methods for applying force or tension on a single protein molecule using tools such as an optical trap or magnetic tweezers and monitoring the conformation of the protein by following the distance between specific sites in the protein. The results will yield observables that can be used directly in theoretical studies of protein folding and the design of the experiments will be carried out in an iterative collaboration with theoreticians in the field. Mechanical stress plays a ubiquitous role in protein function and biology, and therefore, in addition to providing needed insight into the protein-folding problem this work will also provide much needed information about the mechanical stability of proteins.

In addition to its impact in protein folding and macromolecular biophysics, the research in this project requires training at the intersection of physics and biology: the work is a collaborative effort between a physics and a biochemistry lab. The work is not just interdisciplinary; it is actually interdependent, requiring state-of-the-art experiments in both physics and molecular biology. The work requires a combination of students and postdoctoral trainees with diverse backgrounds to work closely together. The project also involves the help of undergraduates, particularly those with a background in engineering and physics, giving them direct exposure to the biological sciences. In sum, this work offers a unique educational experience for the students and post-doctoral fellows involved in the project, and will help to train a new generation of scientists fluent in both the biological and quantitative sciences.

National Science Foundation (NSF)
Division of Molecular and Cellular Biosciences (MCB)
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Kamal Shukla
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University of California Berkeley
United States
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