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. 1995 Jan 31;92(3):753–757. doi: 10.1073/pnas.92.3.753

Rational design of nonnatural peptides as high-affinity ligands for the HLA-B*2705 human leukocyte antigen.

D Rognan 1, L Scapozza 1, G Folkers 1, A Daser 1
PMCID: PMC42698  PMID: 7846047

Abstract

From the three-dimensional structure of the class I major histocompatibility complex (MHC) HLA-B*2705 protein, several nonnatural peptides were designed either to optimize the interactions of one peptide amino acid (position 3) with its HLA binding pocket (pocket D) or to simplify the T-cell receptor-binding part by substitution with organic spacers. The stability of each MHC-ligand complex was simulated by 150-ps molecular dynamics in a water environment and compared with that of the natural complexes. All peptides were synthesized and tested for binding to the class I MHC protein in an in vitro assembly assay. As predicted from the computed atomic fluctuations and buried surface areas of MHC-bound ligands, bulky hydrophobic side chains at position 3 enhance the binding of a nonameric peptide to the HLA-B27 protein. Furthermore, it was possible to simplify half of the peptide sequence (residues 4-8) by replacement with organic fragments without altering the affinity of the designed ligands for the class I MHC protein. This study constitutes an initial step toward the rational design of nonpeptide class I MHC ligands for use in the selective immunotherapy of autoimmune diseases associated with particular HLA alleles.

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Selected References

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