Date of Award

1982

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Abstract

The work presented here is based on the Zimm-Bragg model for the helix-coil transition in polypeptides. Biologically active peptides discussed include: (beta)-endorphin, (beta)-lipotropin, glucagon, secretin, vasoactive intestinal peptide, and the binding or B subunit of cholera toxin. Random copolypeptides studied include copolymers of (omega)-hydroxyethyl and (omega)-hydroxybutyl-L-glutaminyl residues, and ionic copolypeptides containing L-glutamyl and either L-alanyl or L-tyrosyl residues. Residues 17-29 of (beta)-endorphin are expected from calculation to be alpha helical in the presence of anionic lipids. This portion of the chain forms an amphipathic helix which would be expected to interact favorably with a membrane containing anionic lipids. The order of helix formation is predicted to be glucagon < secretin < vasoactive intestinal peptide, which is in agreement with experimental circular dichroism measurements. The region of highest helix propagation probability is residues 13-20. This prediction is in harmony with various experiments by other workers, and this segment of the chain has been implicated in receptor binding for secretin and vasoactive intestinal peptide. A helical hairpin structure is predicted for the B subunit of cholera toxin in sodium dodecyl sulfate. The transition from (beta)-structure to (alpha)-helix occurs over a length of time comparable to the lag period observed in vivo and in vitro. The conformational transition may be related to the pathogenesis of the toxin. The host guest technique was utilized in order to determine (sigma) and s for (omega)-hydroxyethyl-L-glutaminyl residues in water. Hydroxybutyl-L-glutaminyl served as the host residue. A temperature independent value of 1 x 10('-5) was determined for (sigma). The value of s was seen to vary from 0.940 to 4(DEGREES)C to 0.925 at 64(DEGREES)C. The results here are consistent with a smooth decrease in such values from hydroxybutyl to hydroxypropyl to hydroxyethyl-L-glutaminyl residues. The Zimm-Rice theory for the helix-coil transition in charged homopolypeptides was used in an attempt to rationalize circular dichroism and potentiometric titration data for random copolypeptides containing L-glutamyl residues along with either L-alanyl or L-tyrosyl residues. This method was found to fail and no rationalization could be given for adjusting the parameters of the model to bring about agreement. One possible reason may be the model's failure to treat 1-3 and 1-4 interactions.

Pages

184

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