Quantum Chemical Evaluation of NMR Chemical Shifts in Proteins

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The overall goal of this project, jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences and the Computational and Theoretical Chemistry Program in the Chemistry Division, is to use modern quantum mechanics (QM) to provide accurate and unique insights into NMR chemical shifts in biomolecular systems using a continuum representation for the solvent. To reach this overarching goal, the PI will continue to validate and develop his QM based NMR (QM NMR) approach and apply it to biologically relevant problems regarding the structure and dynamics of biomacromolecules. Specifically, the PI will extend the computational efficiency of the QM NMR methodology through the development of a combined QM/molecular mechanics (MM) NMR approach, which will focus the computational effort on the region of interest. He will extend the nuclei that the QM NMR approach can handle to 19F, in order that 19F studies can be carried out to study the structure and dynamics of biological systems. Using the QM NMR approach, the PI developed a method called NMRScore to indicate the fact that he can use NMR chemical shift information in the form of chemical shift perturbations (CSPs) to "score" the position of a small molecule in a protein pocket based on ligand CSPs only. Along with validating NMRScore, the PI will also test a QM/MM based NMRScore in order to validate its efficacy and to demonstrate its superior computational performance over a fully QM based NMRScore protocol. Finally, the PI will use QM NMR to "score" correct versus incorrect protein folds and to also demonstrate its capabilities as a structure validation tool. The intellectual merit of this project is to develop and apply highly sophisticated quantum mechanical tools for the examination of NMR chemical shifts in biological systems. This approach has not been adopted in the past because of the expense of QM based methodologies for systems with 1000's of atoms, but with recent algorithmic and computer hardware advances, one can now tackle biological systems with fully QM models. Structural biologists have also generated an immense amount of data that can be used to validate QM approaches to the study of NMR chemical shifts in biomolecules. This project will train students in formal theory, computer programming, and biological structure and function. This training will prepare them for jobs in either the public or private sector. The PI will distribute his codes to interested parties