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The chemical synthesis of proteins is critical to the understanding of biological function of proteins, particularly those containing posttranslational modifications or involved in covalent protein鈥損rotein conjugates. In order to expand the scope of chemical protein synthesis and to improve the ease with which proteins can be chemically synthesis, our group has sought to identify new ligation reactions that give native peptide bonds under mild, chemoselective conditions.聽 This work has led to the discovery of the alpha-ketoacid鈥揾ydroxylamine amide-forming (KAHA) ligation, which operates in the presence of unprotected functional groups, requires no reagents or catalysts, and proceeds under aqueous conditions.

This talk will describe the development of the KAHA ligation, the reaction mechanism, methods to prepare peptide segments containing the key functional groups, and the application of this reaction to the chemical synthesis of proteins, including challenging targets such as membrane associated proteins. Finally, we will discuss possible solutions to the still unsolved problem of ligating large, unprotected molecules at submillimolar concentrations with equimolar stoichiometry.