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一个多层计算查框架,有效地搜索SARS-CoV-2受体结合动机的突变空间,以识别具有增强ACE2结合能力的突变物

Sandipan Chakraborty¹, Chiranjeet Saha²

¹Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, 500046, India.

Molecular informatics

|August 17, 2023

概括

预测未来的SARS-CoV-2变种至关重要. 研究人员确定了四种受体结合域 (RBD) 突变 (F490K,S494K,G504F,P499L),这些突变显著增强了与人类ACE2的结合,可能会增加传播.

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:

严重急性呼吸系统综合征冠状病毒2 (SARS-CoV-2) 变种在受体结合域 (RBD) 中发生突变,导致了大流行浪潮.
增强的传播和免疫逃避是有关SARS-CoV-2变种的关键特征.

研究的目的:

开发一个计算查平台,以识别SARS-CoV-2 RBD突变与增加的ACE2结合亲和力.
预测潜在的未来变种,增强传播能力.

主要方法:

利用了多层选平台,将分子力学与通用化出生和表面积 (MM/GBSA) 方法,广泛的分子动力学 (MD) 模拟和引导分子动力学 (sMD) 结合起来.
专注于RBD的RBM (受体结合基因) 内的突变,以评估它们对ACE2结合的影响.

主要成果:

确定了四种特定的RBM突变 (F490K,S494K,G504F,P499L),与野生类型相比,显著增强了与人类ACE2的结合.
这些突变导致了更稳定的RBD-ACE2复合体,增加了键和盐桥相互作用.
观察到RBM接口包装的Allosteric调制,导致突变复合体的破裂力更高.

结论:

鉴定的突变 (F490K,S494K,G504F,P499L) 是由于增强的ACE2结合而导致SARS-CoV-2传播增加的潜在驱动因素.
该计算平台为预测未来变种的出现和指导公共卫生战略提供了宝贵的工具.

关键词:

在MM/GBSA中使用.在 RBD-ACE2 界面上.这就是SARS-CoV-2病毒.有约束力的自由能源.突变空间选突变空间选引导了分子动力学.

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