The aim of the proposed research is to determine the three-dimensional structure of a number of peptides (10-30 residues) that perform a variety of functions such as ion transport, analgesia, toxic, antitoxic and antibiotic by means of single crystal X-ray diffraction analysis. These crystals are composed of molecules containing light atoms only, C, N, O and H. The method of solution will be direct phase determination using the tangent formula and a variety of auxiliary formulas. Goals are to continue to design peptide sequences, with a concentration on the production of individual molecules that contain several domains, such as helix/helix reversal/beta sheet. Additional goals are to design beta sheets composed of multiple strands. Considerable success in design, crystallization and structure determination has already been achieved in this laboratory with multiple domains and a variety of beta-sheets. Another area in which effects on conformation are being studied is the insertion or substitution of unusual amino acid residues into a sequence. The unusual amino acid residues already used, or to be used, occur naturally in the lower forms of life (fungi, parasites, bacteria, e.g.) The helix inducing propensity of the Aib residue (dimethyl glycine) has been widely explored in this laboratory in designed peptides, as well as in naturally occurring peptides such as the ionophores antiamoebin and zervamicin, during the current grant period. The emphasis is now turning to beta peptides incorporated into beta-hairpins. The resulting beta-sheets acquire a polarity which is not present in peptides with all alpha-amino residues. Further, the serendipitous formation of hydrophobic pores with diameters >10 Angstroms, by the assembly of 19-mer helices that contain three D-residues, merits further study of both the right-handed helix formation of sequences with so many D-residues and the formation of pores large enough to accommodate and possibly deliver small to medium sized drug molecules. Among X-ray quality crystals on hand are peptides with gamma-amino residues and some with probable multi-stranded beta sheets.
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