Effects of a remote mutation from the contact paratope on the structure of CDR-H3 in the anti-HIV neutralizing antibody PG16
Effects of a remote mutation from the contact paratope on the structure of CDR-H3 in the anti-HIV neutralizing antibody PG16
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DOI：
10.1038/s41598-019-56154-y
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发表时间：
2019-12-27
影响因子：
4.6
通讯作者：
Takano, Yu
中科院分区：
文献类型：
--
作者：
Kondo, Hiroko X.;Kiribayashi, Ryo;Takano, Yu
PG 16是一种针对人类免疫缺陷病毒（HIV）的广泛中和抗体。PG 16的晶体结构显示，异常长的28个残基的互补决定区（CDR）H3形成了一个独特的亚结构域，称为“锤头”，直接接触抗原。锤头状结构显然支配PG 16的功能，而先前的实验测定表明，Tyr（H100 Q）突变为不直接接触抗原的Ala，降低了PG 16的中和能力。然而，来自锤头或接触互补位的远程突变影响中和效力的分子机制仍不清楚。在此，我们对PG 16的野生型和变体（Tyr（H100 Q）至Ala和Tyr（H100 Q）至Phe）进行了分子动力学模拟，以阐明这些突变对CDR-H3动力学的影响。我们的模拟显示，PG 16中CDR-H3的结构刚性可归因于Tyr（H100 Q）和Pro（H99）之间的氢键相互作用以及Tyr（H100 Q）的空间支撑。两种相互作用的丧失增加了PG 16中CDR-H3的内在波动，导致CDR-H3朝向非活性状态的构象转变。
PG16 is a broadly neutralizing antibody to the human immunodeficiency virus (HIV). A crystal structure of PG16 revealed that the unusually long 28-residue complementarity determining region (CDR) H3 forms a unique subdomain, referred to as a "hammerhead", that directly contacts the antigen. The hammerhead apparently governs the function of PG16 while a previous experimental assay showed that the mutation of Tyr(H100Q) to Ala, which does not directly contact the antigen, decreased the neutralization ability of PG16. However, the molecular mechanism by which a remote mutation from the hammerhead or contact paratope affects the neutralization potency has remained unclear. Here, we performed molecular dynamics simulations of the wild-type and variants (Tyr(H100Q) to Ala, and Tyr(H100Q) to Phe) of PG16, to clarify the effects of these mutations on the dynamics of CDR-H3. Our simulations revealed that the structural rigidity of the CDR-H3 in PG16 is attributable to the hydrogen bond interaction between Tyr(H100Q) and Pro(H99), as well as the steric support by Tyr(H100Q). The loss of both interactions increases the intrinsic fluctuations of the CDR-H3 in PG16, leading to a conformational transition of CDR-H3 toward an inactive state.