Theoretical Studies of Protein Folding

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The objective of this project, jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Theoretical and Computational Chemistry Program in the Division of Chemistry in the Mathematical and Physical Sciences Directorate, is to gain an understanding of how inter-residue interactions determine the three-dimensional structure of a globular protein and the pathways from the unfolded polypeptide chain to the final folded conformation. For such an understanding, use is made of a physics-based approach, i.e. one based solely on the global optimization of a potential energy function (including the role of the solvent), without the use of secondary-structure predictions, homology modeling, threading, etc. Such an approach requires both a reliable potential function and an efficient procedure for global optimization; this project is concerned with the development and improvement of the required empirical potential function. Initially, a united-residue (UNRES) potential function is used. UNRES will be improved by crystal calculations, with inclusion of entropy. Then the refined UNRES potential function will be converted to an all-atom treatment by Z-score optimization of the all-atom potential function with inclusion of hydration. The UNRES potential function is being improved by generating decoys with Langevin dynamics and incorporating entropy efforts, using a hierarchical optimization procedure. The all-atom potential function (including a Generalized-Born solvation model) will be improved by the same hierarchical optimization procedure used to improve the UNRES potential function. The search procedures will be carried out by improvement of a Conformational Space Annealing (CSA) method.This research will provide a basic understanding of the role of the inter-residue interactions that determine the conformational and folding properties of proteins, and will provide training, not only for the two co-workers carrying out this research, but also for several postdocs and graduate students working together with these co-workers. Also, as was done during the current project period (when members of the group participated in outreach career exploration by 8th and 9th grade students from schools across New York State), graduate student and postdoc members of the group will participate in the Expanding Your Horizons in Math, Science, and Engineering program of Cornell University for primary school students.