Hierarchical Computational Modeling and Dynamic Network Analysis of Allosteric Regulation in the SARS-CoV-2 Spike Omicron Trimer Structures: Omicron Mutations Cooperate to Allosterically Control Balance of Protein Stability and Conformational Adaptability

Structural and computational studies of the Omicron spike protein in various functional states and complexes provided important insights into molecular mechanisms underlying binding, high transmissibility, and escaping immune defense. However, the regulatory roles and functional coordination of the Omicron mutations are poorly understood and often ignored in the proposed mechanisms. In this work, we explored the hypothesis that the SARS-CoV-2 spike protein can function as a robust allosterically regulated machinery in which Omicron mutational sites are dynamically coupled and form a central engine of the allosteric network that regulates the balance between conformational plasticity, protein stability, and functional adaptability. In this study, we employed coarse-grained dynamics simulations of multiple full-length SARS-CoV-2 spike Omicron trimers structures in the closed and open states with the local energetic frustration analysis and collective dynamics mapping to understand the determinants and key hotspots driving the balance of protein stability and conformational adaptability. We have found that the Omicron mutational sites at the inter-protomer regions form regulatory 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 quantify the allosterically regulated activation mechanism and uncover specific regulatory roles of the Omicron mutations. The network modeling demonstrated that Omicron mutations form the inter-protomer electrostatic bridges that connect local stable communities and function as allosteric switches of signal transmission. The results of this study are consistent with the experiments, revealing distinct and yet complementary role of the Omicron mutational 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.