Theoretical analysis of binding specificity of influenza viral hemagglutinin to avian and human receptors based on the fragment molecular orbital method
Theoretical analysis of binding specificity of influenza viral hemagglutinin to avian and human receptors based on the fragment molecular orbital method
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DOI：
10.1016/j.compbiolchem.2008.03.006
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发表时间：
2008-06-01
影响因子：
3.1
通讯作者：
Tanaka, Shigenori
中科院分区：
文献类型：
--
作者：
Iwata, Tatsunori;Fukuzawa, Kaori;Tanaka, Shigenori
流感病毒的血凝素(HA)蛋白在病毒感染的早期与宿主细胞受体结合。从禽类的α2-3受体到人的α2-6受体的结合特异性的改变对于最佳的人与人之间的传播和大流行至关重要。因此，在分子水平上揭示控制HA-受体复合体结合亲和力的关键因素，对于了解和预测流感大流行具有重要意义。在这项工作中，我们在从头算片段分子轨道(FMO)方法的基础上，进行了HA-受体复合体的相互作用能分析，以定量阐明HAS与禽类和人类受体的结合特异性。为了全面探讨流感病毒血凝素的结合特性，对人H1、猪H1、禽流感H3和禽流感H5病毒的HA进行了分析。我们对各种HA与受体类似物的复合体的相互作用模式进行了详细的研究，发现HA中保守残基之间的分子内相互作用对HA与受体的结合起着重要的作用。这些结果可能为理解受体结合部位保守的酸性残基的作用提供线索，这些残基被唾液酸的静电斥力破坏了稳定性。计算的受体和HA之间的结合能和相互作用模式与每个HA的结合特性相一致，从而解释了受体的结合机制。本分析中的计算结果为与突变残基相关的HA受体结合特异性的模型提供了一些观点。例如，Glu190和Gln226在H5 HA结合特异性中所起的作用。由于H5 HA尚未适应人类受体，其特异性变化的机制尚不清楚，这一结果有助于预测与即将到来的可能的大流行相关的受体特异性的变化。(C)2008爱思唯尔有限公司。保留所有权利。
The hemagglutinin (HA) protein of the influenza virus binds to the host cell receptor in the early stage of viral infection. A change in binding specificity from avian alpha 2-3 to human alpha 2-6 receptor is essential for optimal human-to-human transmission and pandemics. Therefore, it is important to reveal the key factors governing the binding affinity of HA-receptor complex at the molecular level for the understanding and prediction of influenza pandemics. In this work, on the basis of ab initio fragment molecular orbital (FMO) method, we have carried out the interaction energy analysis of HA-receptor complexes to quantitatively elucidate the binding specificity of HAs to avian and human receptors. To discuss the binding property of influenza HA comprehensively, a number of HAs from human H1, swine H1, avian H3 and avian H5 viruses were analyzed. We performed detailed investigations about the interaction patterns of complexes of various HAs and receptor analogues, and revealed that intra-molecular interactions between conserved residues in HA play an important role for HA-receptor binding. These results may provide a hint to understand the role of conserved acidic residues at the receptor binding site which are destabilized by the electrostatic repulsion with sialic acid. The calculated binding energies and interaction patterns between receptor and HAs are consistent with the binding specificities of each HA and thus explain the receptor binding mechanism. The calculated results in the present analysis have provided a number of viewpoints regarding the models for the HA-receptor binding specificity associated with mutated residues. Examples include the role of Glu190 and Gln226 for the binding specificity of H5 HA. Since H5 HA has not yet been adapted to human receptor and the mechanism of the specificity change is unknown, this result is helpful for the prediction of the change in receptor specificity associated with forthcoming possible pandemics. (C) 2008 Elsevier Ltd. All rights reserved.