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Date of Award

2007

Document Type

Thesis - Pacific Access Restricted

Degree Name

Master of Science (M.S.)

Department

Chemistry

First Advisor

Jianhua Ren

First Committee Member

Patrick R. Jones

Second Committee Member

James W. Blankenship

Third Committee Member

C. Michael McCallum

Abstract

Helices in proteins have substantial permanent dipole moments arising from the nearly perfect alignment of the individual dipole moments of each peptide bond. Interaction with this helix "macrodipole" is thought to perturb the pKa values of basic or acidic residues at the helix termini. The goal of this project is to investigate the effect of the helix confonnation on the proton affinities ofbasic amino acids placed at theN- or Ctenninus of helical model peptides in the gas phase. Several series of model peptides having a basic residue, lysine (K) or 2,3- diaminopropionic acid (Dap ), located at either terminus were synthesized by solid phase peptide synthesis using conventional techniques or the amino acid fluoride approach. Proton affinities were determined for several basic amino acids and peptides using mass spectrometry by applying the extended Cooks' kinetic method. Favorable conformations and theoretical proton affinities were probed using computational chemistry. The proton affinities determined for Na-acetyl-(L)-lysine, Ac-AK, Ac-KA, and Ac-KAA are 236.8 ± 1.9 kcal mol-1 , 249.4 ± 2.0 kcal mol-1 , 241.5 ± 1.9 kcal mol-1 , and 244.4 ± 2.0 kcal mol-1 respectively. The large negative entropy changes for each of the peptides upon protonation ( -11.2 to - 21.7 cal mol-1 K- 1 ) are consistent with globular confmmations adopted by the protonated peptides due to extensive intramolecular hydrogen bonding. The measured proton affinities of the peptides increased with the size of the peptide as expected. However, the measured proton affinity of the peptide with C-terminal lysine, Ac-AK, is substantially higher than that of the con·esponding peptide with N-terrninal lysine, Ac-KA, contrary to expectations. Proton affinities determined for these compounds using computational chemistry are in reasonable agreement with experimental results. Additionally, proton affinities calculated for helical polyalanine and Aib (aaminoisobutytic acid) modified polyalanine peptides with C-terminal basic residues (Ac AnK and Ac-(AibA)n-Dap) are much larger than proton affinities calculated for the corresponding peptides with N-terminal basic residues. These results indicate that the helix dipole has a substantial effect on the basicity of residues at the helix termini.

Pages

130

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