Grant: Discovery Grants Program - Individual

State-of-the art computational chemistry will be used to study the formation and reactivities of peptide radical cations, PRC. PRCs are reactive intermediates which are involved in chemical reactions, associated with radiation, oxidative damage, aging, numerous physiological disorders, and enzyme function. Gaseous PRCs are exploited in mass spectrometry for structural determination of polypeptides. Despite their vital importance, the structures and reactivities of PRCs are largely unexplored; the mechanisms of PRC formation remain unclear. The formation of gaseous PRCs upon electron-transfer dissociation (ETD) of Cu(II)(L)M complexes (L=auxiliary ligand, M= peptide) will be examined. The reaction mechanism and the factors controlling the barriers to ETD will be predicted and the rules for the selection of a proper L for a given M in order to maximize the yield of a PRC will be deduced. As a next step, a solvent will be added to the system in order to model the formation of PRCs in vivo. The structures and reactivities of PRCs will be examined using the trends which we determined earlier for the chemistry of radical-cationic amino acids, the building blocks of PRCs. The focus will be on spontaneous/low-energy proton migrations and fragmentations. To date, there is no reliable computational method for conformation searching of PRCs. A robust computational technique based on force field and semi-empirical methods will be developed and verified for exploring flat domains on potential energy surfaces of PRCs. Particularly important domains on the potential energy surface will be treated with ab initio molecular dynamics. The proposed research project will generate significant fundamental knowledge and contribute to our overall understanding of electron-transfer processes and reactivities of radical cations, with direct implications to biochemistry and proteomics.