A comparative molecular similarity indices (CoMSIA) study of peptide binding to the HLA-A3 superfamily

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Abstract

Epitope identification is the basis of modern vaccine design. The present paper studied the supermotif of the HLA-A3 superfamily, using comparative molecular similarity indices analysis (CoMSIA). Four alleles with high phenotype frequencies were used: A*1101, A*0301, A*3101 and A*6801. Five physicochemical properties—steric bulk, electrostatic potential, local hydrophobicity, hydrogen-bond donor and acceptor abilities—were considered and ‘all fields’ models were produced for each of the alleles. The models have a moderate level of predictivity and there is a good correlation between the data. A revised HLA-A3 supermotif was defined based on the comparison of favoured and disfavoured properties for each position of the MHC bound peptide. The present study demonstrated that CoMSIA is an effective tool for studying peptide–MHC interactions.

The motif of the peptides binding to the HLA-A3 superfamily was produced.

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Introduction

Human class I major histocompatibility complex (MHC) molecules are membrane glycoproteins that bind to degraded intracellular antigen fragments, and present them to cytotoxic T lymphocytes (CTL) in order to elicit an immune response.1, 2, 3

The three-dimensional structures of HLA-A2,4 Aw685 and B276 are used as the prototypes for all MHC class I molecules. The major part of the class I molecule is formed by a transmembrane heavy chain of 44 kDa folded into three domains: α1, α2 and α3.7 These domains have been defined by sequence analysis and do not correspond to the two structural domains apparent in the extracellular part of MHC crystal structures. We use this nomenclature to remain consistent with the immunological literature. α1 and α2 form the peptide binding domain which contains the peptide binding groove and the site of interaction with T cell receptors.8, 9 The α3 domain is involved in interactions with CD8.10 Native class I MHCs form a complex with a small polypeptide chain of 12 kDa, called β2-microglobulin. β2-microglobulin is not encoded by an MHC gene.11 Sequence analysis has shown that the peptide domains α1 and α2 are polymorphic, while the α3 domain, the transmembrance and cytoplasmic regions are more conserved. Twenty residues are found to be the most variable.12 Study of the HLA-A2 structure shows that most of the variable residues in the domain form contacts with the peptide, giving the MHC molecule a broad specificity range, allowing it to bind a wide variety of peptides.4

Recently, it was proposed that HLA class I molecules can be grouped into supertypes on the basis of similar peptide-binding characteristics.13 The peptides binding to MHC molecules are called epitopes and the specific arrangement of certain residues along the epitope is called a motif. Four HLA supertypes have been described: A2, A3, B7 and B44.14 The HLA-A3 supertype covers 44% of the human population and includes five main alleles: A*0301, A*1101, A*3101, A*3301 and A*6801.14 The common binding motif (or supermotif) for this supertype is characterised by the presence of a hydroxyl containing (Ser or Thr) or hydrophobic (Leu, Ile, Val or Met) residue at position 2 and a positively charged amino acid (Arg or Lys) at the C-terminus.14

In the present study, we analyse the nature of peptide binding to the A3 supertype using three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis. Comparative molecular similarity indices analysis (CoMSIA)15 was used. In CoMSIA, changes in ligand affinities are directly related to changes in molecular properties.16 This method is good at describing the intermolecular interactions (steric, electrostatic, hydrophobic, hydrogen bond formation) present at the molecular binding site. The method has been used to study the ligand–receptor interactions before and has proved to be of good predictivity.17, 18 In this paper, we apply the method to MHC-peptide interactions. The HLA-A3 superfamily was chosen since it is a relatively large family and has high frequency (>40%) in the general population. The alleles within the family have overlapping specificities. Four members of the A3 family A*1101, A*0301, A*3101 and A*6801 were included in the study. Previously, we applied this method to peptides binding to the HLA-A*0201 allele and found it had a good predictive and explanatory ability.19 More recently, we extended its application to peptides binding to the HLA-A2 supertype and defined a more precise A2-supermotif.20 Now we use the CoMSIA technique to define the position-dependent amino acid preferences for peptides binding to HLA-A3 alleles.

Section snippets

Results

Four sets of peptides, one set per allele, were collected from our JenPep21 database (http://www.jenner.ac.uk/JenPep). Because they were the most common, we used only nonamers in this study of the A3 family. The number of peptides available for alleles A*1101, A*0301, A*3101 and A*6801 were 59, 69, 30 and 39, respectively. Among the selected peptides, some bound to more than one allele. The correlation coefficients between the affinity data for the common peptides range from 0.168 for

Discussion

The motif of HLA-A3 superfamily includes main anchor positions 2 and 9.26 Peptides bound to members of the A3 family usually had a positively charged residue—Arginine or Lysine—at the C terminus, and a variety of hydrophobic residues at position 2. In the present study it was found that steric bulk was favoured at position 2 for A*0301 and A*3101 but disfavoured in A*1101 and A*6801 models. The study of crystal structures of MHC molecules showed that the residue at peptide position 2 bound in

Conclusion

Our 3D-QSAR study has characterised the contribution to A3-supertype binding made at each peptide position with respect to favoured or disfavoured physiochemical properties. Besides the detailed explanatory ability, CoMSIA can also be used for quantitative binding affinity prediction. CoMSIA has proved to be an extremely effective method in describing ligand–receptor interactions in small molecule drug design. The present study demonstrated that it could also be used to characterise binding

Molecular modelling and CoMSIA

No X-ray data was available for a peptide–HLA-A3 molecule complex. As the A2 supertype is the closest to the A3 supertype, a crystallographic structure for the peptide TLTSCNTSV binding to HLA-A*0201 allele was chosen as the starting conformation.23 All molecular modelling calculations were performed on a Silicon Graphics workstation using SYBYL6.724 as previously described.19 Briefly, using the X-ray peptide as a template all the studied peptides were built, energy optimised, their charges

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