In this study, we used an integrative computational approach focused on comparative perturbation-based modeling to examine molecular mechanisms and determine functional signatures underlying role of functional residues in the SARS-CoV-2 spike protein that are targeted by novel mutational variants and antibody-escaping mutations. Atomistic simulations and functional dynamics analysis are combined with alanine scanning and mutational sensitivity profiling for the SARS-CoV-2 spike protein complexes with the ACE2 host receptor are REGN-COV2 antibody cocktail (REG10987+REG10933). Using alanine scanning and mutational sensitivity analysis, we have shown that K417, E484 and N501 residues correspond to key interacting centers with a significant degree of structural and energetic plasticity that allow mutants in these positions to afford the improved binding affinity with ACE2. Through perturbation-based network modeling and community analysis of the SARS-CoV-2 spike protein complexes with ACE2 we demonstrate that E406, N439, K417 and N501 residues serve as effector centers of allosteric interactions and anchor major inter-molecular communities that mediate long-range communication in the complexes. The results provide support to a model according to which mutational variants and antibody-escaping mutations constrained by the requirements for host receptor binding and preservation of stability may preferentially select structurally plastic and energetically adaptable allosteric centers to differentially modulate collective motions and allosteric interactions in the complexes with the ACE2 enzyme and REGN-COV2 antibody combination. This study suggests that SARS-CoV-2 spike protein may function as a versatile and functionally adaptable allosteric machine that exploits plasticity of allosteric regulatory centers to fine-tune response to antibody binding without compromising activity of the spike protein.

中文翻译：

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基于微扰的SARS-CoV-2穗蛋白与宿主受体和中和抗体结合的建模：结构适应性的变构通讯热点定义了以全局循环突变为目标的穗位点

在这项研究中，我们使用了一种基于基于比较扰动的建模的综合计算方法，以检查分子机制并确定SARS-CoV-2穗状蛋白中功能性残基的功能性潜在潜在功能，这些功能性残基被新型突变变体和抗体逃逸靶向突变。原子模拟和功能动力学分析与丙氨酸扫描和突变敏感性分析相结合，用于SARS-CoV-2穗蛋白复合物与ACE2宿主受体为REGN-COV2抗体混合物（REG10987 + REG10933）。通过丙氨酸扫描和突变敏感性分析，我们发现K417，E484和N501残基对应于关键的相互作用中心，具有显着程度的结构和能量可塑性，使这些位置的突变体可提供与ACE2的改进的结合亲和力。通过基于扰动的网络建模以及SARS-CoV-2穗蛋白复合物与ACE2的群落分析，我们证明E406，N439，K417和N501残基充当变构相互作用的效应中心，并锚定了介导长时程相互作用的主要分子间群落。在综合体中进行远程通信。结果为模型提供了支持，根据该模型，受宿主受体结合和稳定性保持要求约束的突变变体和抗体逃逸突变可以优先选择结构可塑性和能量适应性变构中心，以差异地调节复合物中的集体运动和变构相互作用与ACE2酶和REGN-COV2抗体结合。这项研究表明，SARS-CoV-2刺突蛋白可能是一种多功能且功能适应性的变构机器，该机制利用变构调控中心的可塑性来微调对抗体结合的反应，而不会损害刺突蛋白的活性。