Analysis of Binding Modes of Antigen-Antibody Complexes by Molecular Mechanics Calculation
Analysis of Binding Modes of Antigen-Antibody Complexes by Molecular Mechanics Calculation
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DOI：
10.1021/acs.jcim.1c00167
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发表时间：
2021-05
影响因子：
5.6
通讯作者：
Liang Qu;Xinyue Qiao;Fei Qi;N. Nishida;T. Hoshino
中科院分区：
文献类型：
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作者：
Liang Qu;Xinyue Qiao;Fei Qi;N. Nishida;T. Hoshino
抗体是生物药剂学中最重要的蛋白质分子之一。由于生产单克隆抗体的技术的最新进展，许多关于抗原-抗体复合物的结构数据是可用的。为了表征抗原-抗体识别中的分子相互作用，我们通过分子力学计算对500个复杂结构进行了计算分析。Ser和Tyr在互补决定区（CDR）中的存在显著较大。虽然Ser在CDR中丰富，但其对结合得分的贡献并不大。相反，从结合得分的角度来看，Tyr、Asp、Glu和Arg显著地有助于分子相互作用。结合分数的分解表明，与疏水相互作用相比，亲水相互作用在所有CDR中占主导地位。重链的贡献大于轻链的贡献。特别是，H2和H3在很大程度上有助于结合相互作用。Tyr是H2和H3中的主要贡献残基。带正电荷的残基Arg也对H3中的结合得分有显著贡献，而Lys的贡献很小。H2中Ser的出现显著，H3中Asp丰富。不带电荷的极性残基，Thr，Asn和Gln，在H2中出现的比在H3中出现的多。带负电荷的残基Asp和Glu对H3中的结合评分有显著贡献。Phe和Trp的贡献并不大，尽管芳香残基能够进行π-π或CH-π相互作用。Gly通常在H2和H3中都很丰富。抗原和抗体之间的最短直接氢键的平均距离比在化合物和其靶蛋白之间的复合物中观察到的氢键的平均距离长。因此，抗原-抗体界面不如化合物-靶蛋白界面那么紧密。形状互补性的计算与氢键的结果一致，因为抗原-抗体接触的适合度不如化合物-靶蛋白接触的适合度高。在抗原-抗体界面处存在许多水分子。这些发现表明Tyr、Asp、Glu和Arg富含H3，并且作为与抗原相互作用的主要贡献者起作用。Ser、Thr、Asn和Gln富含H2，并支持与增强分子适合度的相互作用。Gly有助于增加灵活性和几何多样性。因为抗原-抗体结合基本上是由蛋白质驱动的，所以非极性残基对于介导接触是不利的，甚至对于芳香族残基如Phe和Trp也是如此。
Antibodies are one of the most important protein molecules in biopharmaceutics. Due to the recent advance in technology for producing monoclonal antibodies, many structural data are available on the antigen-antibody complexes. To characterize the molecular interaction in antigen-antibody recognition, we computationally analyzed 500 complex structures by molecular mechanics calculations. The presence of Ser and Tyr is markedly large in the complementarity-determining regions (CDRs). Although Ser is abundant in CDRs, its contribution to the binding score is not large. Instead, Tyr, Asp, Glu, and Arg significantly contribute to the molecular interaction from the viewpoint of the binding score. The decomposition of the binding score suggests that the hydrophilic interaction is predominant in all CDRs compared with the hydrophobic one. The contribution of the heavy chain is larger than that of the light chain. In particular, H2 and H3 largely contribute to the binding interaction. Tyr is a main contributing residue both in H2 and H3. The positively charged residue Arg also significantly contributes to the binding score in H3, while the contribution of Lys is small. The appearance of Ser is remarkable in H2, and Asp is abundant in H3. The non-charged polar residues, Thr, Asn, and Gln, appear much in H2, compared to appearing in H3. The negatively charged residues Asp and Glu significantly contribute to the binding score in H3. The contributions of Phe and Trp are not large in spite that the aromatic residues are capable of making the π-π or CH-π interaction. Gly is commonly abundant both in H2 and H3. The average distance of the shortest direct hydrogen bond between the antigen and antibody is longer than that of the hydrogen bonds observed in the complexes between compounds and their target proteins. Therefore, the antigen-antibody interface is not so tight as the compound-target protein interface. The calculation of shape complementarity is consistent with the result of the hydrogen bonds in that the fitness of the antigen-antibody contact is not so high as that of the compound-target protein contact. There exist many water molecules at the antigen-antibody interface. These findings suggest that Tyr, Asp, Glu, and Arg are rich in H3 and work as major contributors for the interaction with the antigen. Ser, Thr, Asn, and Gln are rich in H2 and support the interaction with enhancing molecular fitness. Gly is helpful in increasing flexibility and geometrical diversity. Because the antigen-antibody binding is fundamentally hydrophilic-driven, the non-polar residues are unfavorable for mediating the contact even for the aromatic residues such as Phe and Trp.