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QM/MM Study of Epitope Peptides Binding to HLA-A*0201: The Roles of Anchor Residues and Water

Authors

  • Yuanchao Li,

    Corresponding author
    1. 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
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    • These two authors contributed equally to this work.

  • Yadong Yang,

    1. 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
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    • These two authors contributed equally to this work.

  • Ping He,

    1. Cardiothoracic Surgery Department, Southwest Hospital, The Third Military Medical University, Chongqing, China
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  • Qingwu Yang

    Corresponding author
    1. Department of Neurology, Institute of Surgery Research & Daping Hospital, The Third Military Medical University, Chongqing, China
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* Corresponding authors: Yuanchao Li, asiaq2004@163.com and Qingwu Yang, yangqwmlys@hotmail.com

Abstract

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.

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