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 Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, USA.
Int J Mol Sci. 2022 Sep 29;23(19):11542. doi: 10.3390/ijms231911542.
In this study, we performed all-atom MD simulations of RBD-ACE2 complexes for BA.1, BA.1.1, BA.2, and BA.3 Omicron subvariants, conducted a systematic mutational scanning of the RBD-ACE2 binding interfaces and analysis of electrostatic effects. The binding free energy computations of the Omicron RBD-ACE2 complexes and comprehensive examination of the electrostatic interactions quantify the driving forces of binding and provide new insights into energetic mechanisms underlying evolutionary differences between Omicron variants. A systematic mutational scanning of the RBD residues determines the protein stability centers and binding energy hotpots in the Omicron RBD-ACE2 complexes. By employing the ensemble-based global network analysis, we propose a community-based topological model of the Omicron RBD interactions that characterized functional roles of the Omicron mutational sites in mediating non-additive epistatic effects of mutations. Our findings suggest that non-additive contributions to the binding affinity may be mediated by R493, Y498, and Y501 sites and are greater for the Omicron BA.1.1 and BA.2 complexes that display the strongest ACE2 binding affinity among the Omicron subvariants. A network-centric adaptation model of the reversed allosteric communication is unveiled in this study, which established a robust connection between allosteric network hotspots and potential allosteric binding pockets. Using this approach, we demonstrated that mediating centers of long-range interactions could anchor the experimentally validated allosteric binding pockets. Through an array of complementary approaches and proposed models, this comprehensive and multi-faceted computational study revealed and quantified multiple functional roles of the key Omicron mutational site R493, R498, and Y501 acting as binding energy hotspots, drivers of electrostatic interactions as well as mediators of epistatic effects and long-range communications with the allosteric pockets.
在这项研究中，我们对 BA.1、BA.1.1、BA.2 和 BA.3 奥密克戎亚变种的 RBD-ACE2 复合物进行了全原子 MD 模拟，对 RBD-ACE2 结合界面进行了系统的突变扫描，并分析了静电效应。奥密克戎 RBD-ACE2 复合物的结合自由能计算和对静电相互作用的综合分析量化了结合的驱动力，并为奥密克戎变体之间进化差异的能量机制提供了新的见解。对 RBD 残基的系统突变扫描确定了奥密克戎 RBD-ACE2 复合物中的蛋白质稳定性中心和结合能热点。通过采用基于集合的全局网络分析，我们提出了奥密克戎 RBD 相互作用的基于社区的拓扑模型，该模型表征了奥密克戎突变位点在介导突变的非加性上位效应中的功能作用。我们的研究结果表明，对结合亲和力的非加性贡献可能由 R493、Y498 和 Y501 位点介导，并且在奥密克戎 BA.1.1 和 BA.2 复合物中更大，这两种复合物在奥密克戎亚变种中显示出最强的 ACE2 结合亲和力。本研究揭示了反向变构通信的网络中心适应模型，该模型在变构网络热点和潜在变构结合口袋之间建立了稳健的联系。使用这种方法，我们证明了远程相互作用的介导中心可以固定实验验证的变构结合口袋。通过一系列互补的方法和提出的模型，这项全面的多方面计算研究揭示并量化了关键奥密克戎突变位点 R493、R498 和 Y501 的多种功能作用，这些位点作为结合能热点、静电相互作用的驱动因素以及与变构口袋的上位效应和远程通信的介导中心。
