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Side-chain conformational space analysis (SCSA): A multi conformation-based QSAR approach for modeling and prediction of protein–peptide binding affinities

Journal of Computer-Aided Molecular Design volume 23, Article number: 129 (2009) Cite this article

Abstract

In this article, the concept of multi conformation-based quantitative structure–activity relationship (MCB-QSAR) is proposed, and based upon that, we describe a new approach called the side-chain conformational space analysis (SCSA) to model and predict protein–peptide binding affinities. In SCSA, multi-conformations (rather than traditional single-conformation) have received much attention, and the statistical average information on multi-conformations of side chains is determined using self-consistent mean field theory based upon side chain rotamer library. Thereby, enthalpy contributions (including electrostatic, steric, hydrophobic interaction and hydrogen bond) and conformational entropy effects to the binding are investigated in terms of occurrence probability of residue rotamers. Then, SCSA was applied into the dataset of 419 HLA-A*0201 binding peptides, and nonbonding contributions of each position in peptide ligands are well determined. For the peptides, the hydrogen bond and electrostatic interactions of the two ends are essential to the binding specificity, van der Waals and hydrophobic interactions of all the positions ensure strong binding affinity, and the loss of conformational entropy at anchor positions partially counteracts other favorable nonbonding effects.

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  1. Institute of Molecular Design and Molecular Thermodynamics, Department of Chemistry, Zhejiang University, Hangzhou, China

    Peng Zhou, Xiang Chen & Zhicai Shang

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  1. Peng Zhou
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  2. Xiang Chen
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  3. Zhicai Shang
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Correspondence to Zhicai Shang.

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10822_2008_9245_MOESM1_ESM.doc

Supplementary Material Sequences, experimental and calculated binding affinities of 419 HLA-A*0201-restricted CTL epitopes, as well as 26 crystal structures of HLA-A*0201-peptide complexes are provided as supporting information. (DOC 509 kb)

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Zhou, P., Chen, X. & Shang, Z. Side-chain conformational space analysis (SCSA): A multi conformation-based QSAR approach for modeling and prediction of protein–peptide binding affinities. J Comput Aided Mol Des 23, 129 (2009). https://doi.org/10.1007/s10822-008-9245-0

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Keywords

  • Multi-conformation-based quantitative structure–activity relationship
  • Side-chain conformational space analysis
  • Rotamer library
  • Self-consistent mean field theory
  • Protein–peptide complex
  • HLA-A*0201-restricted CTL epitope