The Evolution of Protein Dynamics

The Scripps Research Institute, La Jolla CA

Investigators

Abstract

In this award, funded by the Experimental Physical Chemistry program, Professor Romesberg from The Scripps Research Institute will investigate issues relating to the evolution of protein dynamics. Proteins have evolved to perform their various biological functions that enable life; however, little is understood about how the process of evolution builds proteins for specific functions. One function central to all proteins is molecular recognition - the ability of a protein to find its binding partners within the complex milieu of the cell. Perhaps the single most remarkable system where the evolution of biological molecular recognition may be studied is the immune system, where antibodies (Abs) that recognize virtually any foreign molecule (or antigen, Ag) may be evolved from precursor (or germline) Abs within days of first encounter. The fundamental hypothesis of the proposed research is that the immune system starts with flexible and conformationally heterogeneous germline Abs that can bind a wide range of Ags with an induced-fit mechanism, and then introduces mutations that evolve them into more rigid mature Abs that bind only their target Ag with a lock-and-key mechanism. Thus, Professor Romesberg proposes that during evolution, Abs are selected based in part on a dynamic property, i.e. flexibility. To test this hypothesis, a variety of modern biophysical techniques will be employed, including nonlinear ultrafast laser spectroscopy and NMR spectroscopy, to characterize Ab dynamics and Ag-binding as a function of the specific mutations introduced during evolution. While the proposed research is focused on Abs, it should have important ramifications for how molecular recognition is evolved in other systems, such as with enzymes and their substrates or inhibitors and with signaling cascades and their signaling molecules. In addition to participating in the community outreach programs already in place at TSRI, including hosting high school student interns, presenting seminars, and participating in a lecture series at the Reuben H. Fleet Science Center in San Diego, a summer program for high school educators will be developed to bring the proposed work to a larger audience. The broader impacts of the proposed research are to introduce today's younger scientists, as well as the general public in the San Diego area, to contemporary, interdisciplinary research rooted in the fundamentals of evolution.