Restricted Diversity of Antigen Binding Residues of Antibodies Revealed by Computational Alanine Scanning of 227 Antibody-Antigen Complexes
Restricted Diversity of Antigen Binding Residues of Antibodies Revealed by Computational Alanine Scanning of 227 Antibody-Antigen Complexes
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DOI：
10.1016/j.jmb.2014.08.013
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发表时间：
2014-11-11
影响因子：
5.6
通讯作者：
Martineau, Pierre
中科院分区：
文献类型：
--
作者：
Robin, Gautier;Sato, Yoshiteru;Martineau, Pierre
抗体分子能够以高亲和力和特异性识别任何抗原。为了深入了解这种功能多样性来源的分子多样性，我们编译并分析了227种抗体抗原复合物结构的非冗余对齐集合。所有残基侧链的结合自由能通过计算丙氨酸扫描进行定量，从而首次大规模定量描述抗体互补位。这表明，在30个关键位置中，仅8个残基就足以解释大多数复合物中80%的结合自由能。在这些位置上，残基分布不仅不同于其他表面残基，而且还取决于侧链在相互作用中所起的作用，参与结合能的残基主要是芳香族残基，而Gly或Ser则不然。为了质疑这些结合特征的普遍性，我们通过噬菌体展示使用仅具有两个多样化互补决定区的偏向合成库分离抗体片段，并解决其与抗原复合的结构。尽管这种有限的多样性，结构表明，所有的互补决定区参与与抗原的相互作用，并从天然抗体库的规则适用于这种合成的粘合剂，从而证明了我们的结果的鲁棒性和普遍性。(C)2014作者爱思唯尔有限公司出版
Antibody molecules are able to recognize any antigen with high affinity and specificity. To get insight into the molecular diversity at the source of this functional diversity, we compiled and analyzed a non-redundant aligned collection of 227 structures of antibody antigen complexes. Free energy of binding of all the residue side chains was quantified by computational alanine scanning, allowing the first large-scale quantitative description of antibody paratopes. This demonstrated that as few as 8 residues among 30 key positions are sufficient to explain 80% of the binding free energy in most complexes. At these positions, the residue distribution is not only different from that of other surface residues but also dependent on the role played by the side chain in the interaction, residues participating in the binding energy being mainly aromatic residues, and Gly or Ser otherwise. To question the generality of these binding characteristics, we isolated an antibody fragment by phage display using a biased synthetic repertoire with only two diversified complementarity-determining regions and solved its structure in complex with its antigen. Despite this restricted diversity, the structure demonstrated that all complementarity-determining regions were involved in the interaction with the antigen and that the rules derived from the natural antibody repertoire apply to this synthetic binder, thus demonstrating the robustness and universality of our results. (C) 2014 The Authors. Published by Elsevier Ltd.