| Nature synthesizes all biological proteins by employing repetitive aminoacyl transfer reactions to generate polymers composed of repeating peptide bonds. The research described herein focuses on accelerating aqueous aminoacyl transfer in water and is inspired by two aspects of contemporary protein biosynthesis: first, the potential prebiotic precursors to this process and, second, the possibility of using designed peptides to imitate the essential features of protein biosynthesis. In the first section of this dissertation, the simple triatomic molecules carbonyl sulfide (COS) and carbon disulfide (CS2 ) are demonstrated to effect aminoacyl transfer in water, forming short peptides from amino acid monomers, under a variety of conditions that may have existed before the appearance of life on Earth. Peptide yields can be high depending on the conditions employed. The study of COS in the context of prebiotic chemistry is then expanded to several reactions in which amino acids are first activated by COS and subsequently react with oxygen or sulfur nucleophiles via aminoacyl transfer to form a variety of important non-peptidic products, such as aminoacyl adenylates, nucleoside 2'(3')-esters, and aminoacyl thioacids. Together, these results suggest that peptide formation, phosphorylation, and the syntheses of other amino acid derivatives could have shared a common chemical pathway on the prebiotic Earth. The second section of this dissertation describes the kinetic and structural characterization of coiled-coil peptides that accelerate stoichiometric aminoacyl transfer in aqueous solution by more than six orders of magnitude, mainly by converting the bimolecular reaction into an effectively intramolecular one. The observed rate enhancements illustrate that simple peptide scaffolds can be used to mimic many features of enzymatic catalysis, such as general acid/base catalysis, pKa modulation, and entropic activation of bimolecular reactions. Characterization of these peptides led to the determination of crystal structures for a single coiled-coil peptide in distinct parallel and antiparallel tetrameric configurations, as well as for several related peptide sequences in either the parallel or the antiparallel configuration. Considering the previous examples of structural nonspecificity in coiled-coil peptides, these observations indicate that many coiled-coil sequences may be delicately poised to adopt various quaternary structures that are similar in overall energy. |
