Proteins are linear polymers of roughly twenty natural amino acids, and the
order in which particular amino acids appear along a given protein sequence
determine its folding pattern and the overall shape of its folded or native
conformation. This native conformation in turn controls the function of the
protein in a living organism. A significant piece of the protein folding
puzzle consists in determining how the sequence and amino acid composition
of a medium-sized polypeptide governs the stability of helical conformations
that can be formed from it.
Novel tools have recently been developed that allow this problem to be
addressed incisively. (See: Kemp, D.S.; Allen,T.J.; Oslick, S.; Boyd,
J.G. J. Am. Chem. Soc. (1995) 117 6641-6657. J. Am. Chem
Soc. (1996) 118 4240-4248, 4249-4255.) This work depends on
synthesis and study of novel bioorganic structures that are linked to
normal polypeptides. These conjugates are characterized structurally by
NMR and circular dichroism spectroscopy, as well as by other methods.
Tailored Lifson-Roig matrix algorithms are used to analyze data and model
helical stability. Projects within the scope of this problem involve a
blend of bioorganic chemistry, synthetic organic chemistry, structural
biology, and biophysics.
This research has two tightly coupled aims first, development
of a quantitatively accurate algorithm for predicting helicity from the
amino acid sequence of peptide, and second, design, synthesis, and testing
of "superhelical" analogs of the helix-stabilizing natural amino
acids. These are expected to be uniquely incisive tools for studying a
wide range of problems in medicinal chemistry, biophysics, and structural
biology.
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