From atomic to global connectivity in the structure of the SARS-CoV2-Human ACE2 receptor complex

Abstract

We investigate connectivity properties of the SARS-CoV2 spike protein-human ACE2-receptor complex employing a protein side chain-based network method that allows us to span a range from atomic to global protein scales. We analyze network topology in terms of clusters and cliques obtained from averaging over snapshots of MD simulations (from D.E. Shaw Research). We demonstrate that SARS-CoV2 forms a more dominant, robust connection with the ACE2-receptor as compared to the less virulent SARS-CoV1. Globally, this stronger connectivity is reflected by our percolation analysis where the interface cluster for the SARS-CoV2-ACE2 complex persists when restricted to stronger and stronger bonds, as compared to the SARSCoV1- ACE2 complex. At the atomic level, interface clique structure reflects a stronger connectivity in the former complex. We pinpoint key functional residues in SARSCoV2 that play important roles in establishing this higher connectivity. Thus, our studies provide an objective method to map spatial connectivity of atomic level non-covalent interactions to global connectivity between any two amino acids in the complex. We also analyze specific snapshots of the MD simulations to highlight prominent variations in network topology that explore diverse conformational landscapes. Finally, we demonstrate that a majority of mutations that occur in the SARSCoV2 spike protein in variants of concern/interest (including the currently circulating JN.1) have been observed at the interface with the ACE2 receptor. Our analyses highlight the importance of interface interactions and provide a rationale for designing receptor-like peptides and proteins to combat immunity-escaping variants.