Changes at the floor of the peptide-binding groove induce a strong preference for Proline at position 3 of the bound peptide: Molecular dynamics simulations of HLA-A*0217

Abstract

We report on molecular dynamics simulations of major histocompatibility complex (MHC)–peptide complexes. Class I MHC molecules play an important role in cellular immunity by presenting antigenic peptides to cytotoxic T cells. Pockets in the peptide‐binding groove of MHC molecules accommodate anchor side chains of the bound peptide. Amino acid substitutions in MHC affect differences in the peptide–anchor motifs. HLA‐A*0217, human MHC class I molecule, differs from HLA‐A*0201 only by three amino acid residues substitutions (positions 95, 97, and 99) at the floor of the peptide‐binding groove. A*0217 showed a strong preference for Pro at position 3 (p3) and accepted Phe at p9 of its peptide ligands, but these preferences have not been found in other HLA–A2 ligands. To reveal the structural mechanism of these observations, the A*0217–peptide complexes were simulated by 1000 ps molecular dynamics at 300 K with explicit solvent molecules and compared with those of the A*0201–peptide complexes. We examined the distances between the anchor side chain of the bound peptide and the pocket, and the rms fluctuations of the bound peptides and the HLA molecules. On the basis of the results from our simulations, we propose that Pro at p3 serves as an optimum residue to lock the dominant anchor residue (p9) tightly into pocket F and to hold the peptide in the binding groove, rather than a secondary anchor residue fitting optimally the complementary pocket. We also found that Phe at p9 is used to occupy the space created by replacements of three amino acid residues at the floor within the groove. These findings would provide a novel understanding in the peptide‐binding motifs of class I MHC molecules. © 2000 John Wiley & Sons, Inc. Biopoly 54: 318–327, 2000

Genetic variation of theMHCclassII DRBgenes in the Japanese weasel,Mustela itatsi, endemic to Japan, compared with the Siberian weasel,Mustela sibirica

“…The peptide‐binding domain, which presents a peptide derived from extracellular pathogens, is a heterodimer of an α1‐ and a β1‐domain of the α‐ and β‐chains, respectively. The MHC class II molecules mediate the establishment of acquired immunity by interacting with CD4 molecules on the surface of helper T cells . With some exceptions, the MHC genes are the most polymorphic among vertebrates ; in particular, the residues that compose antigen‐binding sites (ABS) in the β‐chain, encoded by exon 2 of the MHC class II DRB gene, display a high number of alleles, with extensive sequence variation among them .…”

Computational Analysis on the Binding of Epitope Peptide to Human Leukocyte Antigen Class I Molecule A*2402 Subtype

“…49,50) The computational study is also advantageous to analyze the effect of amino acid substitution of epitope peptides. [51][52][53][54] The reason for the change in peptide recognition among different types of HLA molecules has been clearly explained. [55][56][57] In the computational studies, the accurate prediction of the complex structure of HLA and peptide is essentially important and some trials were attempted for the construction of appropriate complex structures.…”

Conformational Flexibility in Designing Peptides for Immunology: The Molecular Dynamics Approach

“…The two alleles differ in three residues at positions 95, 97 and 99 in the -sheet floor of the MHC binding groove. It was found that Pro at position p3 occupying the F binding pocket was an optimum residue to lock the dominant anchor residue (phenylalanine at position p9) tightly into pocket F and to hold the peptide in the binding groove, rather than a secondary anchor residue fitting optimally the complementary pocket [78].…”