Shih-I Pai Lecture

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22nd Annual Shih-I Pai Lecture
"The Folding Cooperativity of a Protein is Controlled by the Topology of its Polypeptide Chain"
by Carlos J. Bustamante

When: Tuesday, October 4, 2016

  • 3:00 pm – Reception in the James A. Yorke Rotunda, Mathematics Building
  • 4:00 pm – Lecture in the Physics Lecture Hall, Room 1412, Physics Building

The Institute for Physical Science and Technology and the Department of Physics presents the 22nd Annual Shih-I Pai Lecture. The Shih-I Pai lecture series commemorates the many contributions and the remarkable legacy of Professor Shih-I Pai (1913-1996), to the study of aerodynamics and fluid dynamics. Professor Pai was a University of Maryland faculty member from 1949 to 1996, and founding member of the Institute for Fluid Dynamics and Applied Mathematics, now the Institute for Physical Science and Technology.

Speaker: Carlos J. Bustamante, Professor of Physics, Chemistry, Molecular and Cell Biology and the Raymond and Beverly Sackler Chair of Biophysics at the University of California, Berkeley.

Biography: Carlos J. Bustamante received his B.S. degree in biology from the Universidad Peruana Cayetano Heredia, Lima, Peru; his M.S. degree in biochemistry from the Universidad Nacional Mayor de San Marcos, Lima, Peru and his Ph.D. in biophysics from the University of California, Berkeley.

Dr. Bustamante is a pioneer in the area of single molecule biophysics. His laboratory develops and applies single-molecule manipulation and detection methods, such as optical tweezers, magnetic tweezers, and single molecule fluorescence microscopy to characterize the dynamics and the mechanochemical properties of various molecular motors that interact with DNA, RNA, or proteins. His lab also uses and develops novel methods for superresolution microscopy to study the organization and function of protein complexes in cells.

Dr. Bustamante is a Fellow of the American Physical Society, an elected member of the National Academy of Sciences, the Chilean Academy of Science and the American Academy of Arts and Sciences. He is a member of the Board of Directors of the American Association for the Advancement of Science. He is the recipient of the Max Delbruck Prize in Biological Physics (2002), the Alexander Hollaender Award in Biophysics (2004), the Richtmyer Memorial Award for physics education (2005), the Vilcek Prize in Biomedical Science (2012), and the Raymond and Beverly Sackler International Prize in Biophysics (2012) for his seminal contributions to single molecule biophysics.

Abstract: Proteins are complex functional molecules that tend to segregate into structural regions. Throughout evolution, biology has harnessed this modularity to carry out specialized roles and regulate higher-order functions such as allostery. Cooperative communication between such protein regions is important for catalysis, regulation, and efficient folding; indeed, lack of domain coupling has been implicated in the formation of fibrils and other misfolding pathologies. How domains communicate and contribute to a protein’s energetics and folding, however, is still poorly understood. Bulk methods rely on a simultaneous and global perturbation of the system (temperature or chemical denaturants) and can miss potential intermediates, thereby overestimating protein cooperativity and domain coupling. I will show that by using optical tweezers it is possible to mechanically induce the selective unfolding of particular regions of single T4 lysozyme molecules and establish the response of regions not directly affected by the force. In particular, I will discuss how the coupling between distinct domains in the protein depends on the topological organization of the polypeptide chain. To reveal the status of protein regions not directly subjected to force, we determined the free energy changes during mechanical unfolding using Crooks’ Fluctuation Theorem. We evaluate the cooperativity between domains by determining the unfolding energy of topological variants pulled along different directions. We show that topology of the polypeptide chain critically determines the folding cooperativity between domains and, thus, what parts of the folding/unfolding landscape are explored. We speculate that proteins may have evolved to select certain topologies that increase coupling between regions to avoid areas of the landscape that lead to kinetic trapping and misfolding.