A graph-based approach identifies dynamic H-bond communication networks in spike protein S of SARS-CoV-2
A graph-based approach identifies dynamic H-bond communication networks in spike protein S of SARS-CoV-2
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DOI：
10.1016/j.jsb.2020.107617
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发表时间：
2020-11-01
影响因子：
3
通讯作者：
Bondar, Ana-Nicoleta
中科院分区：
文献类型：
--
作者：
Karathanou, Konstantina;Lazaratos, Michalis;Bondar, Ana-Nicoleta
冠状病毒刺突蛋白S是一种大分子同源三聚体蛋白，锚定在病毒粒子的膜上。S蛋白与宿主细胞的血管紧张素转换酶2(ACE2)结合，随后SPAKE蛋白发生蛋白降解，随着病毒融合肽的暴露，蛋白构象发生急剧变化，病毒粒子进入宿主细胞。控制Spike蛋白构象可塑性的结构元素在很大程度上是未知的。在这里，我们提出了一种方法，依赖于图形和中心性分析，并辅之以生物信息学，以识别和表征蛋白质结构中的大氢键簇。我们将这种方法应用于蛋白质S胞外结构域，发现在封闭的构象中，蛋白质S的三个原基对广泛的中心氢键网络有相同的贡献，并对称地在受体结合域处形成一个相对较大的氢键簇，并在蛋白酶裂解位点附近贡献一个簇。这三个簇在开放构象和融合前构象中明显不同的氢键表明，动态氢键簇有助于结构可塑性和选择与宿主受体结合的蛋白质S原基，以及蛋白水解性切割。通过对尖峰蛋白序列的分析，我们确定了可能参与瞬时质子结合的组氨酸和羧酸基团的斑块。
Corona virus spike protein S is a large homo-trimeric protein anchored in the membrane of the virion particle. Protein S binds to angiotensin-converting-enzyme 2, ACE2, of the host cell, followed by proteolysis of the spike protein, drastic protein conformational change with exposure of the fusion peptide of the virus, and entry of the virion into the host cell. The structural elements that govern conformational plasticity of the spike protein are largely unknown. Here, we present a methodology that relies upon graph and centrality analyses, augmented by bioinformatics, to identify and characterize large H-bond clusters in protein structures. We apply this methodology to protein S ectodomain and find that, in the closed conformation, the three protomers of protein S bring the same contribution to an extensive central network of H-bonds, and contribute symmetrically to a relatively large H-bond cluster at the receptor binding domain, and to a cluster near a protease cleavage site. Markedly different H-bonding at these three clusters in open and pre-fusion conformations suggest dynamic H-bond clusters could facilitate structural plasticity and selection of a protein S protomer for binding to the host receptor, and proteolytic cleavage. From analyses of spike protein sequences we identify patches of histidine and carboxylate groups that could be involved in transient proton binding.