Keck Center for Science and Engineering, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, USA.
Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, USA.
Phys Chem Chem Phys. 2022 Jul 27;24(29):17723-17743. doi: 10.1039/d2cp01893d.
Dissecting the regulatory principles underlying function and activity of the SARS-CoV-2 spike protein at the atomic level is of paramount importance for understanding the mechanisms of virus transmissibility and immune escape. In this work, we introduce a hierarchical computational approach for atomistic modeling of allosteric mechanisms in the SARS-CoV-2 Omicron spike proteins and present evidence of a frustration-based allostery as an important energetic driver of the conformational changes and spike activation. By examining conformational landscapes and the residue interaction networks in the SARS-CoV-2 Omicron spike protein structures, we have shown that the Omicron mutational sites are dynamically coupled and form a central engine of the allosterically regulated spike machinery that regulates the balance and tradeoffs between conformational plasticity, protein stability, and functional adaptability. We have found that the Omicron mutational sites at the inter-protomer regions form regulatory hotspot clusters that control functional transitions between the closed and open states. Through perturbation-based modeling of allosteric interaction networks and diffusion analysis of communications in the closed and open spike states, we have quantified the allosterically regulated activation mechanism and uncover specific regulatory roles of the Omicron mutations. Atomistic reconstruction of allosteric communication pathways and kinetic modeling using Markov transient analysis reveal that the Omicron mutations form the inter-protomer electrostatic bridges that operate as a network of coupled regulatory switches that could control global conformational changes and signal transmission in the spike protein. The results of this study have revealed distinct and yet complementary roles of the Omicron mutation sites as a network of hotspots that enable allosteric modulation of structural stability and conformational changes which are central for spike activation and virus transmissibility.
解析 SARS-CoV-2 刺突蛋白在原子水平上的功能和活性的调控原则对于理解病毒传播和免疫逃逸的机制至关重要。在这项工作中，我们引入了一种分层计算方法，用于对 SARS-CoV-2 奥密克戎刺突蛋白的变构机制进行原子建模，并提出了基于挫折的变构作为构象变化和刺突激活的重要能量驱动因素的证据。通过检查 SARS-CoV-2 奥密克戎刺突蛋白结构中的构象景观和残基相互作用网络，我们表明奥密克戎突变位点是动态耦合的，并形成了变构调节的刺突机制的核心引擎，调节构象可塑性、蛋白质稳定性和功能适应性之间的平衡和权衡。我们发现，在蛋白间区域的奥密克戎突变位点形成了调节热点簇，控制着闭合和开放状态之间的功能转变。通过对变构相互作用网络进行基于扰动的建模和在闭合和开放刺突状态下的通信扩散分析，我们量化了变构调节的激活机制，并揭示了奥密克戎突变的特定调节作用。通过使用马尔可夫暂态分析进行变构通讯途径的原子重建和动力学建模，揭示了奥密克戎突变形成了蛋白间的静电桥，作为耦合调节开关的网络，可控制刺突蛋白中的全局构象变化和信号传递。这项研究的结果揭示了奥密克戎突变位点作为热点网络的独特而互补的作用，可实现结构稳定性和构象变化的变构调节，这对于刺突激活和病毒传播至关重要。
