A precise three-dimensional chemical structure is generally essential for the function of a protein in the cell. Although ribosomal synthesis generally insures the production of an exact sequence of amino acid residues, such structures are not chemically stable over time. A number of spontaneous processes that occur under physiological conditions, including oxidation, glycation, isomerization, racemization, and deamidation reactions, lead to the alteration, and in some cases, the inactivation of proteins. Asparaginyl and aspartyl residues represent two of the major sites for such reactions in proteins, where intermediate succinimide formation results in the accumulation of L- and D-isoaspartyl and D-aspartyl derivatives. The studies to be performed here are directed at understanding the spontaneous reactions that lead to these altered residues. The goals include the development and testing of models for the succinimide formation in proteins and the analysis of their racemized, deamidated, and isomerized products. By examining known structures of proteins, especially those from thermophilic organisms, The PI hopes to learn how specific folding patterns may decrease the succinimide formation. This should ultimately lead to an understanding of how the accumulation of these derivatives can affect protein structure and how the organism may recognize these altered proteins and catalyze their removal from the cell.
