A comparative molecular similarity index analysis (CoMSIA) study identifies an HLA-A2 binding supermotif

The 3D-QSAR CoMSIA technique was applied to a set of 458 peptides binding to the five most widespread HLA-A2-like alleles: A^*0201, A^*0202, A^*0203, A^*0206 and A^*6802. Models comprising the main physicochemical properties (steric bulk, electron density, hydrophobicity and hydrogen-bond formation abilities) were obtained with acceptable predictivity (q² ranged from 0.385 to 0.683). The use of coefficient contour maps allowed an A2-supermotif to be identified based on common favoured and disfavoured areas. The CoMSIA definition for the best HLA-A2 binder is as follows: hydrophobic aromatic amino acid at position 1; hydrophobic bulky side chains at positions 2, 6 and 9; non-hydrogen-bond-forming amino acids at position 3; small aliphatic hydrogen-bond donors at position 4; aliphatic amino acids at position 5; small aliphatic side chains at position 7; and small aliphatic hydrophilic and hydrogen-bond forming amino acids at position 8.