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在SARS-CoV-2的Omicron BA.2,BA.2.75和XBB血统中平衡蛋白质稳定性和ACE2结合之间的功能性权衡:基于动态的网络模型揭示了模拟补偿动态和能量变化的表态效应

Gennady Verkhivker^1,2, Mohammed Alshahrani¹, Grace Gupta¹

¹Keck Center for Science and Engineering, Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, USA.

|May 27, 2023

概括

这项研究揭示了Omicron突变如何通过特定热点增强SARS-CoV-2稳定性和ACE2结合. 这些发现解释了Omicron的存在.

科学领域:

病毒学病毒学
结构生物学结构生物学
计算生物学计算生物学

背景情况:

由于在免疫逃脱,ACE2结合,稳定性和质调节方面的权衡,Omicron变种表现出体能优势.
了解这些权衡背后的分子机制对于预测病毒演变至关重要.

研究的目的:

系统地描述SARS-CoV-2 Spike Omicron变体 (BA.2,BA.2.75,XBB.1,XBB.1.5) 的结构动态,结构稳定性和ACE2结合亲和力.
确定分子机制和能量热点,从而提高Omicron变体的稳定性和结合性.
分析Omicron Spike-ACE2复合体内的表观相互作用和网络动态.

主要方法:

多尺度分子模拟和动态分析全相互作用.
基于组合的蛋白质残留的突变扫描.
对表观相互作用的网络建模.

主要成果:

在BA.2.75和XBB.1.5变体中确定了特定的能量热点,调解了 BA.2.75和XBB.1.5变体的稳定性和结合亲和力.
由稳定性热点和局部结合亲和中心驱动的机制的特征,允许在其他地方发生中性突变.
提出了基于网络的社区模型,揭示了热点R498和Y501在表观合中的关键作用.
证明F486突变可以重新连接相互作用网络,F486P恢复了XBB.1.5.5.中的稳定性和结合亲和力.

结论:

奥米克朗变异的健康是由协调的热点网络推动的,这些热点平衡了多个健康权衡.
像F486P这样的特定突变可以恢复稳定性和结合性,这可能解释了变体生长优势.
这些发现合理化了Omicron突变部位的功能作用及其对传播能力的贡献.

关键词:

在ACE2宿主受体中,奥米克朗亚型的变种在SARS-CoV-2病毒中,尖蛋白是最常见的.全osteric通讯是指所有的通讯.具有约束力的能源.史诗主义就是一种史诗主义.分子动力学分子动力学突变扫描突变扫描突变扫描网络分析网络分析蛋白质的稳定性蛋白质的稳定性

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