Conformational Eequilibria of Intrinsically Disordered Proteins

Washington University, Saint Louis MO

Investigators

Abstract

The goal of this project is to develop a quantitative framework for conformational equilibria of intrinsically disordered proteins (IDPs), which are a class of functional proteins that are largely unfolded under physiological conditions. Conformational equilibria refer to ensemble average properties and spontaneous fluctuations of IDPs in their native milieus. Important biological functions are associated with intrinsic disorder. These include molecular recognition, self-assembly, post-translational modifications, and entropic machines. The question of how IDPS use disorder in function will remain unanswered pending the availability of accurate, quantitative physical models for conformational equilibria of IDPs. Most IDPs are deficient in hydrophobic residues and are rich in charged and polar residues and therefore they are akin to polyampholytes and polyelectrolytes. Research goals will be accomplished using a combination of techniques including molecular simulations, theoretical approaches based on polymer physics, and fluorescence correlation spectroscopy. The studies will cover a range of IDPs, which differ in their overall hydrophobicity, charge asymmetry, and sequence complexity. Results of these studies will lead to an improved mechanistic understanding of how IDPs use disorder for function. Recent data from the PI's group shows that backbones of generic polypeptides behave like chains in poor solvents in physiological milieus. This observation implies that theories for polyelectrolytes and polyampholytes in poor solvents provide the appropriate conceptual framework for developing quantitative models for conformational equilibria of IDPs. This project will test the hypothesis that IDPs assume conformations akin to so-called necklace globules, which is expected of polyampholytes and polyelectrolytes in poor solvents. Research on IDPs is a major growth area in protein biophysics. The PI's group is developing important tools for the simulation and analysis of conformational and phase equilibria of IDPs. As part of this project, the PI will disseminate these tools to the community, and continue the tradition of using these tools to collaborate with experimentalists. The PI has taken active interest in promoting the cause of IDPs as a major area of research in molecular biophysics. The PI played an important role in helping to draft the statement-of-significance to convince the Biophysical Society's council to create a special subgroup within the society for the discussion of issues central to research on IDPs. The PI is a member of the Biophysics steering committee at Washington University. In this role, the PI is developing stronger ties between biophysics and bioengineering, especially focusing on the areas of IDP function and self-assembly. The PI is also actively involved with the McDonnell International Scholars program at Washington University. One of the goals of this program is to be proactive about recruiting top-flight graduate students and postdoctoral fellows to join research programs at Washington University and contribute to a rich and diverse intellectual environment.