Dynamic Network Modeling of Allosteric Interactions and Communication Pathways in the SARS-CoV-2 Spike Trimer Mutants: Differential Modulation of Conformational Landscapes and Signal Transmission via Cascades of Regulatory Switches

Abstract

The rapidly growing body of structural and biochemical studies of the SARS-CoV-2 spike glycoprotein has revealed a variety of distinct functional states with radically different arrangements of the receptor-binding domain, highlighting a remarkable function-driven conformational plasticity and adaptability of the spike proteins. In this study, we examined molecular mechanisms underlying conformational and dynamic changes in the SARS-CoV-2 spike mutant trimers through the lens of dynamic analysis of allosteric interaction networks and atomistic modeling of signal transmission. Using an integrated approach that combined coarsegrained molecular simulations, protein stability analysis, and perturbation-based modeling of residue interaction networks, we examined how mutations in the regulatory regions of the SARS-CoV-2 spike protein can differentially affect dynamics and allosteric signaling in distinct functional states. The results of this study revealed key functional regions and regulatory centers that govern collective dynamics, allosteric interactions, and control signal transmission in the SARS-CoV-2 spike proteins. We found that the experimentally confirmed regulatory hotspots that dictate dynamic switching between conformational states of the SARS-CoV-2 spike protein correspond to the key hinge sites and global mediating centers of the allosteric interaction networks. The results of this study provide a novel insight into allosteric regulatory mechanisms of SARS-CoV-2 spike proteins showing that mutations at the key regulatory positions can differentially modulate distribution of states and determine topography of signal communication pathways operating through state-specific cascades of control switch points. This analysis provides a plausible strategy for allosteric probing of the conformational equilibrium and therapeutic intervention by targeting specific hotspots of allosteric interactions and communications in the SARS-CoV-2 spike proteins.

Landscape-Based Mutational Sensitivity Cartography and Network Community Analysis of the SARS-CoV-2 Spike Protein Structures: Quantifying Functional Effects of the Circulating Variants

“…Using this framework, the residue interaction networks in the SARS-CoV-2 spike trimer structures were built using a graph-based representation of protein structures in which residue nodes are interconnected through both dynamic 83 and coevolutionary correlations. 84,85 Using community decomposition, the residue interaction networks were divided into local interaction modules in which residues are densely interconnected and highly correlated, while the local communities are weakly coupled through long-range allosteric couplings. A community-based model of allosteric communications is based on the notion that groups of residues that form local interacting communities are correlated and switch their conformational states cooperatively.…”

Computational Analysis of Protein Stability and Allosteric Interaction Networks in Distinct Conformational Forms of the SARS-CoV-2 Spike D614G Mutant: Reconciling Functional Mechanisms through Allosteric Model of Spike Regulation

“…According to our latest study of the SARS-CoV-2 S mutant trimers, this hydrophobic center is coupled with the Y855/I856 conformational switch that mediate couplings between the S2 subunit and the RBD regions. 118 Interestingly, the HR1 region (residues 934-940) is also known to be targeted by naturally occurring mutations in SARS-CoV-2 protein. 119,120 In the open state of the S-D614 spike protein, we observed notable changes in the distance fluctuation profile, particularly indicating the loss of appreciable peaks near the D614 cluster ( Figure 7B).…”

Atomistic Simulations and Deep Mutational Scanning of Protein Stability and Binding Interactions in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Molecular Determinants of Mutational Escape Mechanisms

“…The copyright holder for this preprint (which this version posted July 8, 2021. ; https://doi.org/10.1101/2021.07.07.451538 doi: bioRxiv preprint 8 MD simulations with coevolutionary analysis and network modeling to present evidence that the SARS-CoV-2 spike protein function as allosterically regulated machine that exploits plasticity of allosteric hotspots to fine-tune response to antibody binding. [77][78][79][80][81][82] These studies showed that examining allosteric behavior of the SARS-CoV-2 pike proteins may be useful to uncover functional mechanisms and rationalize the growing body of diverse experimental data.…”