Towards incorporation of catalytic function into small folded peptide scaffolds

This thesis describes the development of iterative and combinatorial methods for identifying small peptide scaffolds able to support catalytic function. The incorporation of thiamine coenzyme functionality into small peptide scaffolds is achieved through the use of a coenzyme amino acid chimera (Taz). This thiazole amino acid can be alkylated to generate the active thiazolium species. A series of designed peptides containing the Taz coenzyme chimera revealed that an increasingly structured and hydrophobic peptidyl environment can dramatically enhance the acidity of the thiazolium C2 methine, the initial step in the catalytic pathway. A combinatorial approach is developed to permit a more rapid screening of large libraries of ppa peptide sequences for unique functional properties. The method used a fluorescent 13-diketone probe to identify a family of similar sequences that incorporate a functional primary amine at the center of the hydrophobic core of the PPa peptide structure. The function of the amine is enhanced by the provision of the hydrophobic peptidyl environment and is able to modestly enhance aldol condensation and retro-aldol reactions. Finally, a new trimeric Apa oligomer structure is evaluated as a functional peptide scaffold. Initially, the structural requirements of the motif are explored through a series of sequence modifications. These studies lead to the incorporation of a primary amine at a unique site in the scaffold that greatly enhances the reactivity of the amine. It is further demonstrated that this increased functional ability is directly related to the folded stability of the trimer.

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Chemistry

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2001

Author dc:creator

• McDonnell, Kevin A. (Kevin Andrew), 1973-

Advisor dc:contributor.advisor

• Barbara Imperiali.

• Chemistry.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/8626

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/8626