• anchor residue;
  • HLA-A*0201;
  • peptide;
  • QM/MM;
  • water

A hybrid quantum mechanics/molecular mechanics scheme is described to explore the structural basis and energetic behavior of short peptide segments binding to HLA-A*0201. This method was used to analyze 50 structurally diverse non-americ peptides and results showed that the quantum mechanics/molecular mechanics-derived interaction energy, in conjugation with empirical desolvation free energy, linearly correlate well with the experimentally determined affinity. Further systematic investigations of several HLA-A*0201–peptide complexes confirmed the importance of anchor residues and water molecules in peptide binding, and quantitatively showed that: (i) the primary and second anchor residues provide a larger binding energy contribution (>3 kcal/mol) than the non-anchor residues (<2 kcal/mol), (ii) native hydrophobic anchor residues replaced by polar amino acids will lead to a significant destabilization for bound complexes (>4 kcal/mol), and (iii) water molecules contribute significantly to stabilization of the complexes (>8 kcal/mol). We believe that this work is helpful for elucidating the roles of anchor residues and water molecules in peptides recognized and bound by HLA-A*0201.