QM/MM study of epitope peptides binding to HLA-A*0201: the roles of anchor residues and 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.
State Key Laboratory of Trauma, Burns and Combined Injury, Department NO.1, Institute of Surgery Research & Daping Hospital, The Third Military Medical University, Chongqing, China. asiaq2004@163.com
Yuanchao
Y
Li
Yadong
Y
Yang
Ping
P
He
Qingwu
Q
Yang
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015234:HLA-A Antigens / Q000737:chemistry* / Q000378:metabolism; D015789:HLA-A2 Antigen; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D013816:Thermodynamics; D014867:Water / Q000737:chemistry / Q000502:physiology*
D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides; D014867:Water