Keck Center for Science and Engineering, Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, USA.
Department of Chemistry, Center for Research Computing, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, TX 75275, USA.
Viruses. 2023 Oct 10;15(10):2073. doi: 10.3390/v15102073.
In the current study, we explore coarse-grained simulations and atomistic molecular dynamics together with binding energetics scanning and cryptic pocket detection in a comparative examination of conformational landscapes and systematic characterization of allosteric binding sites in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB.1 spike full-length trimer complexes with the host receptor ACE2. Microsecond simulations, Markov state models and mutational scanning of binding energies of the SARS-CoV-2 BA.2 and BA.2.75 receptor binding domain complexes revealed the increased thermodynamic stabilization of the BA.2.75 variant and significant dynamic differences between these Omicron variants. Molecular simulations of the SARS-CoV-2 Omicron spike full-length trimer complexes with the ACE2 receptor complemented atomistic studies and enabled an in-depth analysis of mutational and binding effects on conformational dynamic and functional adaptability of the Omicron variants. Despite considerable structural similarities, Omicron variants BA.2, BA.2.75 and XBB.1 can induce unique conformational dynamic signatures and specific distributions of the conformational states. Using conformational ensembles of the SARS-CoV-2 Omicron spike trimer complexes with ACE2, we conducted a comprehensive cryptic pocket screening to examine the role of Omicron mutations and ACE2 binding on the distribution and functional mechanisms of the emerging allosteric binding sites. This analysis captured all experimentally known allosteric sites and discovered networks of inter-connected and functionally relevant allosteric sites that are governed by variant-sensitive conformational adaptability of the SARS-CoV-2 spike structures. The results detailed how ACE2 binding and Omicron mutations in the BA.2, BA.2.75 and XBB.1 spike complexes modulate the distribution of conserved and druggable allosteric pockets harboring functionally important regions. The results are significant for understanding the functional roles of druggable cryptic pockets that can be used for allostery-mediated therapeutic intervention targeting conformational states of the Omicron variants.
在当前的研究中，我们结合粗粒化模拟和原子分子动力学，以及结合能扫描和隐匿口袋检测，对 SARS-CoV-2 奥密克戎 BA.2、BA.2.75 和 XBB.1 刺突全长三聚体复合物与宿主受体 ACE2 的构象景观进行了比较研究，并对别构结合位点进行了系统表征。微秒模拟、马科夫状态模型和 SARS-CoV-2 BA.2 和 BA.2.75 受体结合结构域复合物结合能的突变扫描揭示了 BA.2.75 变体的热力学稳定性增加，以及这些奥密克戎变体之间的显著动力学差异。SARS-CoV-2 奥密克戎刺突全长三聚体复合物与 ACE2 受体的分子模拟补充了原子研究，并使我们能够深入分析突变和结合效应对奥密克戎变体构象动态和功能适应性的影响。尽管结构相似，但奥密克戎变体 BA.2、BA.2.75 和 XBB.1 可以诱导独特的构象动态特征和构象状态的特定分布。使用 SARS-CoV-2 奥密克戎刺突三聚体复合物与 ACE2 的构象集合，我们进行了全面的隐匿口袋筛选，以研究奥密克戎突变和 ACE2 结合对新兴别构结合位点分布和功能机制的作用。该分析捕获了所有实验已知的别构位点，并发现了由 SARS-CoV-2 刺突结构的变体敏感构象适应性控制的相互连接和功能相关的别构位点网络。结果详细说明了 ACE2 结合和 BA.2、BA.2.75 和 XBB.1 刺突复合物中的奥密克戎突变如何调节保守和可成药的别构口袋的分布，这些口袋包含功能重要区域。这些结果对于理解可成药隐匿口袋的功能作用具有重要意义，可用于针对奥密克戎变体构象状态的别构介导治疗干预。
