Studying the Origin of Conformational Preferences in Unfolded Proteins

Washington University, Saint Louis MO

Investigators

Abstract

The objective of this project is to develop a predictive model for the experimentally observed conformational preferences of unfolded proteins. Tiffany and Krimm proposed that unfolded proteins are an ensemble of conformations, each built of local segments that fluctuate in an uncorrelated manner about left-handed polyproline II (PII) helices. Recent experimental results support this hypothesis. PII-like conformations are preferred for a variety of model peptides in water, although the PII-content itself varies with amino acid sequence, solvent, and temperature. How are these preferences realized in the absence of cooperative interactions that stabilize the folded state? For over four decades the random-coil model has been the dominant paradigm for unfolded proteins. This model does not help explain the origin of specific local conformational preferences, nor does it offer insights into the role of such preferences for protein folding and stability. It is imperative that an appropriate framework be developed to account for the experimentally observed preferences of unfolded proteins. Such an endeavor is of crucial importance in understanding the physical principles that underlie the evolution of foldable and functional amino acid sequences. Recent results suggest that there are two distinct determinants of conformational preferences in unfolded proteins. The realization of distinct conformational basins is mainly determined by excluded volume effects. Conversely, the relative stabilities of these conformational basins encoded by steric considerations can be noticeably modulated by solvation and other thermodynamic parameters such as temperature and pressure. The goal of this research is to study the PII content of short model peptides and small proteins as a function of amino acid sequence, chain length, and milieu. To this end, molecular simulations based on both simple and sophisticated all-atom potential functions will be performed. The validity of all theoretical calculations will be tested by comparisons with experimental data. The PI is actively involved in recruiting and training undergraduate and graduate students in areas of biophysics, bioengineering, and computational biology. The course contents are cross-disciplinary and students who take the courses come from a variety of disciplines ranging from the basic to applied sciences. The PI is also actively working on the design of novel algorithms, ideas, and tools for molecular simulation. Computational technologies developed in the PI's group have been and will continue to be integrated with resources that are made available to the scientific community by members of the Center for Computational Biology at Washington University.