Prediction of the Quaternary Structure and Folding Thermodynamics of Multimeric Helical Proteins

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Skolnick, JMCB 9986019 The long-term objectives of this research are the development of algorithms capable of predicting the quaternary structure of small oligomeric helical proteins as well as to provide qualitative insights into their thermodynamic properties. To accomplish these goals, the lattice models developed by Skolnick and Kolinski will be reparameterized to better reproduce the balance of secondary and tertiary interactions, denatured state properties will be simulated to insure that they are treated appropriately, and the quaternary structure and folding thermodynamics of simple, multimeric helical proteins will be predicted. In particular, using Entropy Sampling Monte Carlo, the quaternary structures of coiled coils such as the GCN4 leucine zipper, its fragments, sequences designed by Hodges, and ROP-based dimers will be examined.Many proteins only assume their biologically active conformation on association to multimers. For example, the leucine zipper motif present in eukaryotic gene regulatory proteins is one of the three known modes by which regulatory proteins recognize and bind DNA. Obviously, the ability to predict their quaternary structure is of practical importance. In contrast to the substantial body of experimental work, there are few theoretical studies on these important systems. The research described here is aimed at addressing this need in coiled coils and in somewhat more complicated multimeric helical proteins, such as ROP. Such studies are the first steps in the understanding on a molecular level of metabolic and signaling pathways.This project is jointly supported by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences and the Theoretical Physical Chemistry Program in the Division of Chemistry.