Glycan Cluster Shielding and Antibody Epitopes on Lassa Virus Envelop Protein
Glycan Cluster Shielding and Antibody Epitopes on Lassa Virus Envelop Protein
复制标题
拉沙病毒包膜蛋白上的聚糖簇屏蔽和抗体表位
DOI：
10.1021/acs.jpcb.0c11516
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Mizuguchi Kenji
中科院分区：
文献类型：
--
作者：
Re Suyong;Mizuguchi Kenji
了解抗病毒单克隆抗体如何识别其靶标对于中和抗体和疫苗的开发至关重要。病毒蛋白的广泛糖基化几乎肯定会影响抗体反应，但由于其固有的复杂性和灵活性，表面聚糖的巨大结构和相互作用范围阻碍了对这种影响的研究。在这里，我们建立了一个完全糖基化的拉沙病毒包膜蛋白复合物的原子模型，并进行了分子动力学模拟来表征表面聚糖对抗体反应的影响。模拟证明了表面聚糖的各种构象和相互作用。结果表明，糖基化不均匀地屏蔽了复合物的表面，对蛋白质动力学的影响很小。聚糖通过与蛋白质残基的相互作用聚集成不同的簇，只有少数区域能被抗体接触到。通过将模拟结果与现有的基于序列和结构的表位预测方法相结合，我们成功地恢复了已知的蛋白质表位。结果强调了聚糖丰富的结构环境，并表明屏蔽不仅仅是由均匀的糖毯包裹。这项工作为将难以捉摸的聚糖结构特性整合到疫苗和中和抗体开发中提供了分子基础。
An understanding of how an antiviral monoclonal antibody recognizes its target is vital for the development of neutralizing antibodies and vaccines. The extensive glycosylation of viral proteins almost certainly affects the antibody response, but the investigation of such effects is hampered by the huge range of structures and interactions of surface glycans through their inherent complexity and flexibility. Here, we built an atomistic model of a fully glycosylated envelope protein complex of the Lassa virus and performed molecular dynamics simulations to characterize the impact of surface glycans on the antibody response. The simulations attested to the variety of conformations and interactions of surface glycans. The results show that glycosylation nonuniformly shields the surface of the complex and only marginally affects protein dynamics. The glycans gather in distinct clusters through interaction with protein residues, and only a few regions are left accessible by an antibody. We successfully recovered known protein epitopes by integrating the simulation results with existing sequence- and structure-based epitope prediction methods. The results emphasize the rich structural environment of glycans and demonstrate that shielding is not merely envelopment by a uniform blanket of sugars. This work provides a molecular basis for integrating otherwise elusive structural properties of glycans into vaccine and neutralizing antibody developments.