In SARS-CoV2, we evaluated the mutations in Spike protein by means of a graph representation derived from extensive all-atom molecular dynamics simulations of the wild-type, as well as a mutant, in two different conformations of the Receptor Binding Domain (RBD) (“one-up” and “all-down”). Using network analysis techniques including node centralities and pathlengths measures, we examined the role of individual residues in each of the different network configurations. We have identified residues that are more effective at bridging spatially distant regions of the Spike. These residues, therefore, represent potential targets that can alter essential long-range molecular interactions and stability. Network analysis also shows distal positions that are associated with an enhancement of allostery towards the infection-capable conformation RBD.<br/>The envelope proteins from several high-risk viral pathogens, such as HIV, SARS-CoV2, and Ebola, have dynamic and dense sugar (glycan) coating effectively acts as a shield for the underlying protein. Specially in HIV, the surface exposed glycoprotein remains the immunological target but the glycan shield presents a problem for neutralizing antibody-based vaccine development. We have integrated a high-throughput atomistic modeling with graph-theory based method to capture the glycan shield topological network in HIV envelope, pinpoint potential interaction pathways, and identify concerted behavior of these glycans. This graph was validated with cryo-EM measurements of glycosylated protein exhibiting hierarchical structure and connectivity.

Quantifying and analyzing the effect of viral protein mutations and glycosylations using graph theory

ACS Spring Meeting 2021

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