Rapid ultra-sensitive three dimensional protein structure determination by mass s

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DESCRIPTION (provided by applicant): Protein structure is directly connected to proper cellular function and offers a molecular level understanding of the biochemical pathways related to health or disease. This project will develop a method for examining protein structure in the gas phase. This will be accomplished by modifying a state of the art mass spectrometer with a tunable UV laser capable of generating novel protein radicals. Observation of the dissociation patterns of these radical proteins will reveal a series of distance constraints that can be leveraged into three dimensional structures with the aid of molecular dynamics simulations. This method will allow the advantages of speed, sensitivity, and flexibility which are highly optimized for the mass spectrometric analysis of proteins to be applied to the challenging area of structure determination. Therefore, many target proteins which would be intractable for traditional methods will now be viable targets for structure elucidation. Initial systems that will be investigated include proteins that are related to Parkinson's disease and cancer. It is anticipated that knowledge of the structures of these proteins and factors that influence their structures will greatly facilitate drug development and eventual treatments. PUBLIC HEALTH RELEVANCE (provided by applicant): Proteins are, at a molecular level, the machines which the human body uses to carry out most biological processes. Revealing the nature of these machines, including their exact structure, is critical to understanding the causes, responses, and potential cures for virtually any disease. This project will develop a novel method for determining the structures of proteins that will greatly expand the number of proteins that can be examined including targets related to cancer and Parkinson's disease.