Structure of Peptides that Inhibit Pertussis Toxin-Receptor Binding

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Dr. Spangler proposes to study the molecular basis for recognition of receptor ligands by bacterial toxins, characterizing the amino acid residues and structural conformation of the toxin's receptor- binding site and modeling the receptor-toxin interaction with conformationally restrained peptides. This goal will be accomplished in part by a combination of computer-assisted molecular modeling and experimental binding studies of specific peptide fragments recently shown to inhibit pertussis toxin binding to receptor analogs. To initiate this study and facilitate the molecular dynamics portion of the project, three-dimensional structural information for these peptides will be required, coupled with an experimental determination of the binding characteristics of the peptides. The proposed preliminary study will consist of: (a) peptide structure prediction by computational methods (b) peptide structure solution by NMR methods (c) computer modeling of peptide interaction with receptor analogs (d) experimental verification of the ability of the peptides to bind receptor analogs and to block the binding of the intact toxin %%% The long range goal is to explore protein-ligand interactions and provide a rational basis for understanding and manipulating molecular recognition in both binding functions and protein folding. The techniques and information developed are of value in prediction of receptor structures to aid design of drugs, herbicides or pesticides; antigens in vaccine design; or novel molecules, such as catalytic antibodies and new molecular electronic devices based on proteins, that can be developed by protein engineering to provide a template for catalysis or electron transfer.