PDF(Pubmed)
Abstract：
With the COVID-19 pandemic continuing, more contagious SARS-CoV-2 variants, including Omicron, have been emerging. The mutations, especially those that occurred on the spike (S) protein receptor-binding domain (RBD), are of significant concern due to their potential capacity to increase viral infectivity, virulence, and breakthrough antibodies\' protection. However, the molecular mechanism involved in the pathophysiological change of SARS-CoV-2 mutations remains poorly understood. Here, we summarized 21 RBD mutations and their human angiotensin-converting enzyme 2 (hACE2) and/or neutralizing antibodies\' binding characteristics. We found that most RBD mutations, which could increase surface positive charge or polarity, enhanced their hACE2 binding affinity and immune evasion. Based on the dependence of electrostatic interaction of the epitope residue of virus and docking protein (like virus receptors or antibodies) for its invasion, we postulated that the charge and/or polarity changes of novel mutations on the RBD domain of S protein could affect its affinity for the hACE2 and antibodies. Thus, we modeled mutant S trimers and RBD-hACE2 complexes and calculated their electrotactic distribution to study surface charge changes. Meanwhile, we emphasized that heparan sulfate proteoglycans (HSPGs) might play an important role in the hACE2-mediated entry of SARS-CoV-2 into cells. Those hypotheses provide some hints on how SARS-CoV-2 mutations enhance viral fitness and immune evasion, which may indicate potential ways for drug design, next-generation vaccine development, and antibody therapies.
摘要：
随着COVID-19大流行的继续，传染性更强的SARS-CoV-2变种，包括Omicron,已经出现了。突变，尤其是那些发生在刺突（S）蛋白受体结合域（RBD），由于它们增加病毒感染性的潜在能力，毒力,和突破性的抗体保护。然而,SARS-CoV-2突变病理生理改变的分子机制仍然知之甚少。这里,我们总结了21个RBD突变及其人血管紧张素转换酶2(hACE2)和/或中和抗体的结合特性.我们发现大多数RBD突变,这可能会增加表面正电荷或极性，增强其hACE2结合亲和力和免疫逃避。基于病毒表位残基与对接蛋白（如病毒受体或抗体）的静电相互作用对其入侵的依赖性，我们推测S蛋白RBD结构域上新突变的电荷和/或极性变化会影响其对hACE2和抗体的亲和力。因此，我们对突变体S三聚体和RBD-hACE2复合物进行了建模，并计算了它们的电分布以研究表面电荷的变化。同时,我们强调硫酸乙酰肝素蛋白聚糖（HSPG）可能在hACE2介导的SARS-CoV-2进入细胞中起重要作用。这些假设提供了一些关于SARS-CoV-2突变如何增强病毒适应性和免疫逃避的提示，这可能表明药物设计的潜在方法，下一代疫苗的开发，和抗体疗法。
