Theoretical Studies of Protein Folding

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Intellectual Merit The intellectual merit and the goal of this activity is not, primarily, to predict the structures of biomolecules such as proteins and nucleic acids but, rather to improve the potential functions and algorithms to be able to gain an understanding of how inter-residue interactions determine the three-dimensional structure of, for example, a globular protein and the pathways from the unfolded polypeptide chain to the final folded (native) conformation (the protein folding problem). For such an understanding, use is made of a physics-based approach, i.e., one based solely on the global optimization of a free energy function based on potential energy and on recently-introduced entropy effects (including the role of the solvent) without the use of secondary-structure predictions, homology modeling, threading, etc. The main focus of this project is the extension of the united-residue (UNRES) methodology to treat protein-DNA and protein-protein enzyme-substrate complexes. To accomplish this there will be the final development of UNRES, the treatment of various environments with UNRES, treatment of protein structures at the all-atom level, the development of a coarse-grained model of nucleic acids, the treatment of protein-nucleic acid and protein-protein complexes, the development of sampling and analysis algorithms and the validation of UNRES and nucleic acid-UNRES protocols.Broader ImpactThe broader impacts resulting from the project are that the theoretical approach will provide a basic understanding of the conformational thermodynamic, and folding properties of bio-macromolecules and their interaction with each other and will provide training, not only for the co-workers carrying out this research, but also for several postdocs and visiting scientists working together with these coworkers. A web server (CheShift), available at http://cheshift.com to enable NMR spectroscopists to obtain theoretical C(alpha)-13 chemical shifts to validate their structures, is provided.This project is receiving co-funding from the Chemistry of Life Processes program in the Chemistry Division