Collagen is the principle structural protein in vertebrates. Defects in collagen have been associated with a wide variety of diseases, and knowledge of the atomic basis for the structure and stability of collagen is an important step in developing treatments for these diseases. The structure of collagen is stabilized by hydroxylation of certain proline residues. The means by which the hydroxyl stabilizes the structure is not clearly understood. Preliminary evidence supports a hypothesis in which the inductive effect of the hydroxyl favors the trans conformation of the proline, which is necessary for proper folding of the collagen triple helix. The proposed research will test this hypothesis as follows. 1) Several halogenated collagen mimics will be synthesized containing fluorine, chlorine, bromine, or iodine in place of the hydroxyl on the modified proline. 2) The 4(R)-hydroxyls of a collagen-like peptide will be modified with the electron-withdrawing acetyl, mesyl, or trifluoromethyl groups. 3) The thermodynamics and energetics of all of the synthesized or modified peptides will be measured and correlated to the thermodynamics and kinetics of cis-trans isomerization of the peptide bonds of related small molecules.
