Network analysis uncovers the communication structure of SARS-CoV-2 spike protein identifying sites for immunogen design

Highlights

• The main hubs of communication of the protein are located in the NTD and CT0 regions

• The D614G variant is more resilient to disruption than the ancestral form

• Empirical model validation shows that a N317P substitution could impact ACE2 binding

• A network analysis approach could guide the design of effective immunogens

Summary

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered myriad efforts to understand the structure and dynamics of this complex pathogen. The spike glycoprotein of SARS-CoV-2 is a significant target for immunogens as it is the means by which the virus enters human cells, while simultaneously sporting mutations responsible for immune escape. These functional and escape processes are regulated by complex molecular-level interactions. Our study presents quantitative insights on domain and residue contributions to allosteric communication, immune evasion, and local- and global-level control of functions through the derivation of a weighted graph representation from all-atom MD simulations. Focusing on the ancestral form and the D614G-variant, we provide evidence of the utility of our approach by guiding the selection of a mutation that alters the spike’s stability. Taken together, the network approach serves as a valuable tool to evaluate communication “hot-spots” in proteins to guide design of stable immunogens.