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Design of enhanced agonists through the use of a new virtual screening method: Application to peptides that bind class I major histocompatibility complex (MHC) molecules

¹ Institut de Recerca Biomèdica de Barcelona, Parc Científic de Barcelona, E-08028 Barcelona, Spain
² Illinois Genetic Algorithms Laboratory, Department of General Engineering, University of Illinois, Urbana, Illinois 61801, USA
³ Departament de Química Orgànica, Universitat de Barcelona, E-08028 Barcelona, Spain

(RECEIVED January 11, 2005; FINAL REVISION May 12, 2005; ACCEPTED May 17, 2005)

A new screening procedure is described that uses docking calculations to design enhanced agonist peptides that bind to major histocompatibility complex (MHC) class I receptors. The screening process proceeds via single mutations of one amino acid at the positions that directly interact with the MHC receptor. The energetic and structural effects of these mutations have been studied using fragments of the original ligand that vary in length. The results of these docking studies indicate that the mutant affinity ranking of long peptides can be practically reproduced with a screening approach performed using fragments of six residues. Fragments of four and five residues could mimic, in some cases, the structural arrangement of the side chains of the full-length peptide. We have compared the structural and energetic results of the docking calculations with experimental data using three unrelated ligand peptides that differ greatly in their affinity for the MHC complex. Analysis of the affinity of the fragments led to the identification of three important parameters in the construction of fragments that mimic the structural and energetic properties of the full-length ligand: the length of the fragment; its intermolecular energy; and the number and localization, internal or terminal, of the anchor residues. The results of this new peptide-design methodology have been applied to suggest new peptides derived from the MUC1–8 peptide that could be used as murine vaccines that trigger the immune response through the MHC class I protein H-2K^b.

Keywords: docking calculations; MHC–peptide interactions; virtual screening; peptide vaccine design; MUC1; tumor immunotherapy; H-2K^b; MHC class I

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051351605.

Reprint requests to: Ernest Giralt, Institut de Recerca Biomèdica de Barcelona, Parc Cientific de Barcelona, Josep Samitier 1–5, 08028 Barcelona, Spain; e-mail: egiralt{at}pcb.ub.es; fax: 34-93-4037126.

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