Graduate Program in Computational and Data Sciences, Keck Center for Science and Engineering, Schmid College of Science and Technology, Chapman University, One University Drive, Orange, California 92866, United States.
Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, California 92618, United States.
J Proteome Res. 2020 Nov 6;19(11):4587-4608. doi: 10.1021/acs.jproteome.0c00654. Epub 2020 Oct 2.
The development of computational strategies for the quantitative characterization of the functional mechanisms of SARS-CoV-2 spike proteins is of paramount importance in efforts to accelerate the discovery of novel therapeutic agents and vaccines combating the COVID-19 pandemic. Structural and biophysical studies have recently characterized the conformational landscapes of the SARS-CoV-2 spike glycoproteins in the prefusion form, revealing a spectrum of stable and more dynamic states. By employing molecular simulations and network modeling approaches, this study systematically examined functional dynamics and identified the regulatory centers of allosteric interactions for distinct functional states of the wild-type and mutant variants of the SARS-CoV-2 prefusion spike trimer. This study presents evidence that the SARS-CoV-2 spike protein can function as an allosteric regulatory engine that fluctuates between dynamically distinct functional states. Perturbation-based modeling of the interaction networks revealed a key role of the cross-talk between the effector hotspots in the receptor binding domain and the fusion peptide proximal region of the SARS-CoV-2 spike protein. The results have shown that the allosteric hotspots of the interaction networks in the SARS-CoV-2 spike protein can control the dynamic switching between functional conformational states that are associated with virus entry to the host receptor. This study offers a useful and novel perspective on the underlying mechanisms of the SARS-CoV-2 spike protein through the lens of allosteric signaling as a regulatory apparatus of virus transmission that could open up opportunities for targeted allosteric drug discovery against SARS-CoV-2 proteins and contribute to the rapid response to the current and potential future pandemic scenarios.
开发用于定量描述 SARS-CoV-2 刺突蛋白功能机制的计算策略对于加速发现针对 COVID-19 大流行的新型治疗药物和疫苗至关重要。结构和生物物理研究最近对 SARS-CoV-2 刺突糖蛋白的预融合形式的构象景观进行了特征描述，揭示了一系列稳定和更动态的状态。本研究采用分子模拟和网络建模方法，系统地研究了功能动力学，并确定了野生型和 SARS-CoV-2 预融合刺突三聚体突变体不同功能状态下变构相互作用的调节中心。本研究表明，SARS-CoV-2 刺突蛋白可以作为变构调节引擎，在动态不同的功能状态之间波动。基于扰动的相互作用网络建模揭示了效应热点在受体结合域和 SARS-CoV-2 刺突蛋白融合肽近端区域之间的串扰在相互作用网络中的关键作用。结果表明，SARS-CoV-2 刺突蛋白相互作用网络中的变构热点可以控制与病毒进入宿主受体相关的功能构象状态之间的动态切换。本研究通过变构信号作为病毒传播的调节装置，从变构信号的角度为 SARS-CoV-2 刺突蛋白的潜在机制提供了一个有用的新视角，为针对 SARS-CoV-2 蛋白的靶向变构药物发现提供了机会，并有助于对当前和潜在的未来大流行情况做出快速反应。
