PMID: 9443342Jan 27, 1998Paper

Structure-based thermodynamic design of peptide ligands: application to peptide inhibitors of the aspartic protease endothiapepsin

Proteins
I LuqueE Freire

Abstract

The prediction of binding affinities from structure is a necessary requirement in the development of structure-based molecular design strategies. In this paper, a structural parameterization of the energetics previously developed in this laboratory has been incorporated into a molecular design algorithm aimed at identifying peptide conformations that minimize the Gibbs energy. This approach has been employed in the design of mutants of the aspartic protease inhibitor pepstatin A. The simplest design strategy involves mutation and/or chain length modification of the wild-type peptide inhibitor. The structural parameterization allows evaluation of the contribution of different amino acids to the Gibbs energy in the wild-type structure, and therefore the identification of potential targets for mutation in the original peptide. The structure of the wild-type complex is used as a template to generate families of conformational structures in which specific residues have been mutated. The most probable conformations of the mutated peptides are identified by systematically rotating around the side-chain and backbone torsional angles and calculating the Gibbs potential function of each conformation according to the structural parametriz...Continue Reading

References

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Citations

Jul 26, 2000·Proceedings of the National Academy of Sciences of the United States of America·H Ye, H Wu
Aug 25, 2004·Proteins·Arya Akmal, Victor Muñoz
May 21, 1999·Proteins·B K ShoichetI D Kuntz
Sep 5, 2002·Proteins·Irene Luque, Ernesto Freire
Aug 23, 2003·The Journal of Biological Chemistry·Sonia Huecas, José Manuel Andreu

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