Surveying the Side-Chain Network Approach to Protein Structure and Dynamics: The SARS-CoV-2 Spike Protein as an Illustrative Case

Abstract

Network theory-based approaches provide valuable insights into the variations in global structural connectivity between different dynamical states of proteins. Our objective is to review network-based analyses to elucidate such variations, especially in the context of subtle conformational changes. We present technical details of the construction and analyses of protein structure networks, encompassing both the non-covalent connectivity and dynamics. We examine the selection of optimal criteria for connectivity based on the physical concept of percolation. We highlight the advantages of using side-chain-based network metrics in contrast to backbone measurements. As an illustrative example, we apply the described network approach to investigate the global conformational changes between the closed and partially open states of the SARS-CoV-2 spike protein. These conformational changes in the spike protein is crucial for coronavirus entry and fusion into human cells. Our analysis reveals global structural reorientations between the two states of the spike protein despite small changes between the two states at the backbone level. We also observe some differences at strategic locations in the structures, correlating with their functions, asserting the advantages of the side-chain network analysis. Finally, we present a view of allostery as a subtle synergistic-global change between the ligand and the receptor, the incorporation of which would enhance drug design strategies.

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

“…These new unique hubs at the S1-S2 interfacial regions in combination with the common hubs in the N2R linker region (T315, F318, R319, and R328) form a subnetwork that stabilizes connections between the NTD and RBD regions and the CTD1 and CTD2 domains. Similar to other network-centric analyses of the SARS-CoV-2 S trimers (Halder et al, 2020) we observed some variance in the distribution of hubs in different protomers due to the inherent asymmetry in the residue interaction networks across subunits. Structural maps of the network hubs on the structures of the S-D614 and S-G614 mutant trimers highlighted the broad distribution of mediating residues across S1 and S2 domains (Figure 8).…”

“…Notably, the closed and open forms of the S-D614 and S-G614 structures can share a number of conserved hub positions that are largely determined by the topology of the spike trimer (Figure 7C). Interestingly, these common hubs are very similar to the conserved network hubs reported for cryo-EM structures of the SARS-CoV-2 spike S trimer in the closed state (K986P/ V987P,) (pdb id 6VXX) and open state (pdb id 6VYB) (Halder et al, 2020). Among conserved hub positions are residues proximal or directly aligned with the hinge sites shared by closed and open forms including T315, F318, R319, R328, V539, F592, and Y612 located near the D614 mutational site.…”

“…The network parameters were computed using the python package NetworkX (Hagberg et al, 2008) and Cytoscape package for network analysis (Shannon et al, 2003). The community and hub analyses in the SARS-CoV-2 S-D614 and S-G614 structures are used as proxy for measuring allosteric communications between subdomains and inter-protomer association in the SARS-CoV-2 S structures (Halder et al, 2020).…”

Network analysis outlines strengths and weaknesses of emerging SARS-CoV-2 Spike variants

“…While some previous studies have implemented similar network-based approaches to on relatively shorter simulations with the aim of identifying overall subdomains and hubs in the Spike [55][56][57], our analysis provides detailed and new insights into the communication structure and the control cores of the protein at large. We identify a critical communication ring connecting peripheral regions of the protein, such as the NTD supersite, the up-RBD, and the furin cleavage sites, to each other as well as to the core of the protein, where crucial processes take place upon host receptor binding (e.g.…”

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

“…This analysis provides also a global metric to measure changes in connectivity and interaction between subdomains and inter-protomer association in the SARS-CoV-2 S structures. 95…”