Crystallographic Structure Determination/Refinement Using Atomic Electron Density Functions, and Optimization of Appropriate Force Fields for Analysis

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This project will develop (1) methods to facilitate macromolecular structure determination and improve its accuracy, and, (2) methods to determine force field parameters appropriate for prediction of variants of known structure of proteins and viruses. Central to these efforts to improve crystallographic structure determination is exploitation of a method to quickly calculate the expected electron density of an atom in a way that for the first time accounts fully for the resolution limit of the experiment. Refinement methods that optimize the agreement between model and experimental electron density will be developed further. The electron density function will also be applied to the placement of trial atoms in the Shake-and-Bake direct method of phase determination. The development of real-space refinement will lead to a more precise description of atomic structure. The research into force fields will allow much more reliable prediction of the effects of modifications upon structure. Together, these advances will greatly facilitate the determination of which atomic interactions are critical for catalysis, specificity and for other functions in many systems.