通过将候选适应性多态与蛋白质动力学集成,SARS-COV-2尖端蛋白质的分子适应的某些机械基础
Nicholas J Ose1, Paul Campitelli1, Tushar Modi1
1Department of Physics and Center for Biological Physics, Arizona State University, Tempe, Arizona, United States of America.
bioRxiv : the preprint server for biology
|September 25, 2023
概括
在SARS-CoV-2中的候选自适应多态 (CAPs) 尖端蛋白通过全控制影响人类ACE2结合. 奥米克龙突变与CAPs相互作用,帮助抗体逃逸.
科学领域:
- 分子生物学分子生物学
- 进化生物学 进化生物学
- 病毒学 病毒学
背景情况:
- SARS-CoV-2 Spike (S) 蛋白对于病毒进入至关重要,也是适应性进化的关键目标.
- 了解S蛋白的分子适应对于开发有效的治疗方法和疫苗至关重要.
研究的目的:
- 通过将进化预测与蛋白质动态相结合,研究SARS-CoV-2尖端蛋白的分子适应.
- 确定候选适应多态 (CAP) 并阐明它们对HACE2结合和病毒进化的功能影响.
主要方法:
- 应用了分子进化的中性理论来预测SARS-CoV-2 S蛋白中的CAPs.
- 利用蛋白质动态分析来评估CAPs对S蛋白功能的影响以及与人类ACE2 (hACE2) 的相互作用.
- 分析了不同SARS-CoV-2菌株 (三角形,欧米克龙) 的特征突变,以确定动态标志和表观相互作用.
主要成果:
- 识别了经常与已知的S蛋白的功能部位重叠的CAP.
- 证明了CAPs和haCE2结合位点之间的关键基相互作用,CAPs控制了开放S蛋白形状中的结合残留动态.
- 发现Delta变种和CAPs之间的非添加性 (表观性) 相互作用,与Omicron菌株中的添加性突变形成鲜明对比.
- 揭示了Omicron突变与CAPs发生表观相互作用,有助于抗体逃逸.
结论:
- CAPs在SARS-CoV-2尖刺蛋白对HACE2结合的全性控制中发挥着重要作用.
- 在SARS-CoV-2菌株之间,S蛋白突变的动态不同,这对病毒病原和免疫逃避有影响.
- 新型突变和CAP之间的表观相互作用是Omicron抗体逃逸的关键机制,突出显示了对病毒进化的持续监测的必要性.
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