CATALYZED AMIDE ISOMERIZATION: SYNTHETIC ROTAMASES

点击翻译按钮获取中文摘要

DESCRIPTION; The goal of this proposal is to disvover mild, selective catalysts for amide isomerization (AI), culminating in the systematic development of model rotamase enzymes that catalyze the folding of peptides through the cis-trans isomerization of proline residues. The PI indicates that in turn he proposes experiments that address various individual facets of rotamase catalysis, including metal iion catalysis; catalysis by desolvation; catalysis by distortion; and autocatalysis and that finally he integrates these diverse concepts together into a proposal for synthetic rotamases using the strategy of molecular imprintation, wherein a synthetic template molecule, or "hapten", is complexed non-covalently with a modified crosslinking reagent, the template assemblies are then copolymerized with suitable nomomers to produce highly cros-linked, macroporous polymers and template molecules are removed to leave beha=ind rigid cavities able to recognize amides which resemble the template in terms of shape, or more recognize amides which resemble the template in terms of shape, or more subtly, hydrogen bond donor or acceptor ability. It is noted that since the template is designed to closely mimic the transition state for AI (especially proline isomerization), the polymer would serve as a totally synthetic rotamase enzyme. Preliminary data include the first documented cases of metal ion catalyzed AI, employing substoichiometric amounts of metal under mild conditions; general acid-catalyzed AI; autocatalysis in model systems; and miceelle-catalyzed AI, which for the first tiem models the effects of enzymatic desolvation on rotamase activity. The PI notes that his primary objective is to understand in detail the various complex factors dictating rotamase catalysis, to apply his preliminary results to problems in organic synthesis, and to catalyze the folding of increasingly complex systems including polypeptides and eventually proteins. He suggests that aside from the fundamental understanding of rotamase catalysis that this study will help achieve, practical applications include the development of novel enantioselective transformaitons.