Verkhivker Gennady M, Agajanian Steve, Kassab Ryan, Krishnan Keerthi
Keck Center for Science and Engineering, Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, California 92866, United States.
Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, California 92618, United States.
J Chem Inf Model. 2022 Apr 25;62(8):1956-1978. doi: 10.1021/acs.jcim.2c00124. Epub 2022 Apr 4.
The structural and functional studies of the SARS-CoV-2 spike protein variants revealed an important role of the D614G mutation that is shared across many variants of concern (VOCs), suggesting the effect of this mutation on the enhanced virus infectivity and transmissibility. The recent structural and biophysical studies provided important evidence about multiple conformational substates of the D614G spike protein. The development of a plausible mechanistic model that can explain the experimental observations from a more unified thermodynamic perspective is an important objective of the current work. In this study, we employed efficient and accurate coarse-grained simulations of multiple structural substates of the D614G spike trimers together with the ensemble-based mutational frustration analysis to characterize the dynamics signatures of the conformational landscapes. By combining the local frustration profiling of the conformational states with residue-based mutational scanning of protein stability and network analysis of allosteric interactions and communications, we determine the patterns of mutational sensitivity in the functional regions and sites of variants. We found that the D614G mutation may induce a considerable conformational adaptability of the open states in the SARS-CoV-2 spike protein without compromising the folding stability and integrity of the spike protein. The results suggest that the D614G mutant may employ a hinge-shift mechanism in which the dynamic couplings between the site of mutation and the interprotomer hinge modulate the interdomain interactions, global mobility change, and the increased stability of the open form. This study proposes that mutation-induced modulation of the conformational flexibility and energetic frustration at the interprotomer interfaces may serve as an efficient mechanism for allosteric regulation of the SARS-CoV-2 spike proteins.
对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突蛋白变体的结构和功能研究揭示了D614G突变的重要作用，该突变在许多关注变体（VOCs）中都有出现，表明该突变对病毒感染性和传播性增强有影响。最近的结构和生物物理研究提供了关于D614G刺突蛋白多种构象亚态的重要证据。从更统一的热力学角度开发一个合理的机制模型来解释实验观察结果是当前工作的一个重要目标。在本研究中，我们对D614G刺突三聚体的多种结构亚态进行了高效且准确的粗粒度模拟，并结合基于系综的突变受挫分析来表征构象景观的动力学特征。通过将构象状态的局部受挫分析与基于残基的蛋白质稳定性突变扫描以及变构相互作用和通讯的网络分析相结合，我们确定了变体功能区域和位点的突变敏感性模式。我们发现，D614G突变可能会在不损害刺突蛋白折叠稳定性和完整性的情况下，诱导SARS-CoV-2刺突蛋白开放状态产生相当大的构象适应性。结果表明，D614G突变体可能采用一种铰链移位机制，其中突变位点与原体间铰链之间的动态耦合调节域间相互作用、整体流动性变化以及开放形式稳定性的增加。本研究提出，突变诱导的原体间界面构象灵活性和能量受挫的调节可能是SARS-CoV-2刺突蛋白变构调节的一种有效机制。
