Mutational landscape and in silico structure models of SARS-CoV-2 spike receptor binding domain reveal key molecular determinants for virus-host interaction

BMC Molecular and Cell Biology, Journal Year: 2022, Volume and Issue: 23(1)

Published: Jan. 7, 2022

Abstract Background SARS-CoV-2, the causative agent of COVID-19 pandemic is a RNA virus prone to mutations. Formation stable binding interface between Receptor Binding Domain (RBD) SARS-CoV-2 Spike (S) protein and Angiotensin-Converting Enzyme 2 (ACE2) host pivotal for viral entry. RBD has been shown mutate frequently during pandemic. Although, few mutations in exhibit enhanced transmission rates leading rise new variants concern, most show sustained ACE2 infectivity. Yet, how all these make constantly favourable remain enigmatic. This study aims delineate molecular rearrangements mutants. Results Here, we have generated mutational structural landscape first six months We analyzed 31,403 genomes randomly across globe, identified 444 non-synonymous that cause 49 distinct amino acid substitutions contact non-contact residues. Molecular phylogenetic analysis suggested independent emergence Structural mapping on Wuhan reference strain comparison with RBDs from bat-CoV, SARS-CoV, pangolin-CoV, bound human or mouse ACE2, revealed several changes interfacial interactions three clusters. Interestingly, mediated via N487 residue cluster-I Y449, G496, T500, G502 residues cluster-III remained largely unchanged Further showed are evolutionarily conserved sarbecoviruses which use Importantly, despite extensive interface, RBD-ACE2 stability affinities were maintained Taken together, findings reveal uses its remodel interface. Conclusion Our broadly signifies understanding virus-host interfaces their alterations propose possible remodelling mechanism used by escape deleterious Future investigations will focus functional validation in-silico investigating mechanisms sarbecoviruses. Thus, long run, this may provide novel clues therapeutically target pan-sarbecovirus infections.

Language: Английский

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Structural effects of spike protein D614G mutation in SARS-CoV-2

Biophysical Journal, Journal Year: 2022, Volume and Issue: 122(14), P. 2910 - 2920

Published: Nov. 17, 2022

A single mutation from aspartate to glycine at position 614 has dominated all circulating variants of the severe acute respiratory syndrome coronavirus 2. D614G induces structural changes in spike (S) protein that strengthen virus infectivity. Here, we use molecular dynamics simulations dissect effects and 630-loop rigidification on S-protein structure. The introduction orders structure thereby global toward cryoelectron microscopy S-protein. ordered weakens local interactions between 614th residue others contrast disordered structures wild-type protein. allosterically alters receptor-binding domains, forming an asymmetric mobile down conformation facilitating transitions up conformation. loss salt bridge D614 K854 upon generally stabilizes protomer, including fusion peptide proximal region mediates membrane fusion. Understanding basis is crucial as it dominates concern, Delta Omicron.

Language: Английский

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Deep Structural Analysis of Myriads of Omicron Sub-Variants Revealed Hotspot for Vaccine Escape Immunity

Vaccines, Journal Year: 2023, Volume and Issue: 11(3), P. 668 - 668

Published: March 15, 2023

The emergence of the Omicron variant has reinforced importance continued SARS-CoV-2 evolution and its possible impact on vaccine effectiveness. Specifically, mutations in receptor-binding domain (RBD) are critical to comprehend flexibility dynamicity viral interaction with human agniotensin-converting enzyme 2 (hACE2) receptor. To this end, we have applied a string deep structural genetic analysis tools map substitution patterns S protein major sub-variants (n = 51) primary focus RBD mutations. This head-to-head comparison revealed multiple simultaneous that attributed antibody escape, increased affinity binding hACE2. Our mapping matrix indicated high level diversity at N-terminal domains compared other regions protein, highlighting these two matched vaccination approach. Structural identified highly variable up confirmation sites critically define function virus pathobiology. These substitutional trends offer support tracking along evolutionary trajectories SAR-CoV-2. Collectively, findings highlight areas across propose several hotspots proteins train future design development COVID-19 vaccines.

Language: Английский

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Mechanisms of allostery at the viral surface through the eyes of molecular simulation

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 84, P. 102761 - 102761

Published: Dec. 23, 2023

Language: Английский

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Epistasis between N-terminal and receptor-binding domains drives cell entry in a bat coronavirus spike

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 27, 2024

Understanding the zoonotic risks posed by bat coronaviruses (CoVs) is critical for pandemic preparedness. Herein, we generated recombinant vesicular stomatitis viruses (rVSVs) bearing spikes from divergent CoVs to investigate their cell entry mechanisms. Unexpectedly, successful recovery of rVSVs spike SHC014, a SARS-like CoV, was associated with acquisition novel substitution in S2 fusion peptide-proximal region (FPPR). This enhanced viral both VSV and coronavirus contexts increasing availability receptor-binding domain recognize its cellular receptor, ACE2. A second N-terminal domain, uncovered through forward-genetic selection, interacted epistatically FPPR synergistically enhance spike:ACE2 interaction entry. Our findings identify genetic pathways adaptation during spillover host-to-host transmission, fitness trade-offs inherent these pathways, potential Achilles' heels that could be targeted countermeasures.

Language: Английский

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