Elucidating the role of disorder during biomolecular fuction

Abstract

Understanding the relationship between structure, energetics and functional dynamics of proteins is a major challenge in molecular biophysics. In this project, we will bring together a bi-national, multi-institutional team of leading research groups that will aim to reveal how molecular disorder is utilized during biological function. In particular, we will investigate how partial transient disorder is linked to large-scale conformational transitions in Ras GTPase and estrogen receptor ligand-binding domain. Through the combined efforts of X-ray crystallography and mutagenesis, EPR spectroscopy and molecular simulations, we will elucidate the molecular determinants that govern large-scale conformational transitions associated with function in these proteins. By studying both proteins, we anticipate that insights into the role of disorder during function, and the tools for characterizing disorder, will be transferrable. Accordingly, scientific finding for each system will be mutually beneficial, allowing our team to draw more broad insights into the physical-chemical principles that regulate biological dynamics. (AU)