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bioRxiv · 10.1101/2021.06.15.448568

Deep Mutational Scanning of Dynamic Interaction Networks in the SARS-CoV-2 Spike Protein Complexes: Allosteric Hotspots Control Functional Mimicry and Resilience to Mutational Escape

Verkhivker, G.
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Abstract

We develop a computational approach for deep mutational scanning of residue interaction networks in the SARS-CoV-2 spike protein complexes to characterize mechanisms of functional mimicry and resilience to mutational escape by miniprotein inhibitors. Using a dynamic mutational profiling and sensitivity analysis of protein stability, binding interactions and global network parameters describing allosteric signaling, we identify regulatory hotspots in the SARS-CoV-2 S complexes with the ACE2 host receptor and ultra-potent miniproteins. The results revealed that global circulating variants are associated with allosteric control points that are dynamically coupled to structural stability hotspots. In this mechanism, variant-induced perturbations of flexible allosteric sites can result in global network changes and elicit specific protein responses. The binding affinity fingerprints and allosteric signatures of the SARS-CoV-2 complexes with miniproteins are determined by a dynamic cross-talk between regulatory control points and conformationally adaptable allosteric hotspots that collectively control structure-functional mimicry, signal transmission and resilience to mutational escape.

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Verkhivker, G.. 2021-06-15. Deep Mutational Scanning of Dynamic Interaction Networks in the SARS-CoV-2 Spike Protein Complexes: Allosteric Hotspots Control Functional Mimicry and Resilience to Mutational Escape. https://doi.org/10.1101/2021.06.15.448568

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