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Current Topics in Peptide & Protein Research   Volumes    Volume 1  Issue 2
A common structural feature enclosing interaction sites: Prediction of protein-protein interaction sites and development of potent bioactive peptides
R. Manjunatha Kini, Herbert J. Evans
Pages: 297 - 311
Number of pages: 15
Current Topics in Peptide & Protein Research
Volume 1  Issue 2

Copyright © 1994 Research Trends. All rights reserved

Protein-protein interactions are specific and high affinity interactions due to molecular recognition sites found on the surface. Here we review our recent findings on a common structural feature enclosing these sites. We have shown that the probability of finding proline residues in the flanking segments of interaction sites is two to three times that predicted from their random  distribution. The unique chemistry of proline residues can account for their proposed structural role. Proline residues break the continuity of any secondary structure of the flanking regions and protect the conformation and integrity of interaction sites. They set the interaction sites apart by inducing kinks and bends. Thus, proline brackets facilitate protein-protein interaction. We exploited this finding in two orthogonal directions. Firstly, we developed a simple predictive method for identifying interaction sites directly from amino acid sequence data. Using this method we identified a fibrin polymerization site. The synthetic peptide HPGIAEFPSRA (amino acids represented by their single letter code) comprising this predicted site inhibited the coagulation of human blood and allosterically interfered in fibrin polymerization. This is the first known allosteric polymerization site. This method should contribute significantly to the study of structure-function relationships of proteins. We describe the advantages and limitations of this predictive method. Secondly, we propose a novel approach to the design and development of more potent peptide drugs and ligands. We incorporated proline residues on either or both sides of the interaction site of an antiplatelet peptide, IARGDMNA, and determined the inhibitory potency of the peptides in whole blood aggregation. Incorporation of a proline residue on one side enhances the antiplatelet activity by 1.5 to 2.5 fold, whereas incorporation on both sides enhances the activity by 7 to 13 fold. This enhancement is due to proper presentation of the site and/or a reduction in the number of possible conformations of the peptide. Unlike cyclization, proline brackets allow more flexibility of the interaction site. Both of these applications provide strong support for the structural role of proline brackets near protein-protein interaction sites.
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