Snapshot of Proteins in Action:

Elucidating Freeze-Trapped Intermediates with Solid State Nuclear Magnetic Resonance

This proposal provides a strategic plan to develop and implement a novel technique
which will dramatically increase the quality and quantity of the experimental data available for the further development of protein folding models and simulations. During the completion of my postdoctoral term, I will employ a novel solid state NMR method I have developed to investigate the structural details of proteins in a frozen snapshot of the conformations existing in solution. These results will then be quantitatively used to refine molecular dynamics (MD) simulation methods via the use of quantum chemical methods. Once the folding models have been improved, I will study intermolecular reactions in the context of enzymes to elucidate structural mechanisms of disease as an assistant professor. These valuable methods can then be used for the development of effective new drug targets by measuring and simulating the details of structural activity which I plan to pursue throughout my academic career.

The proposed plan of research effectively has two stages: The first stage (postdoctoral) will lay the foundation for a new snapshot solid state NMR method by characterizing the equilibrium folding process of some small model proteins for the evaluation of folding
models and computational methods. The second stage (faculty) will elucidate the kinetic folding of these same model proteins with the snapshot method and then progress to the study of enzymes and details of their activity to further push the abilities of computational methods for the elucidation of drug target modeling.