JMB-S-21-00552

Molecular dynamics simulation files for in-review JMB-S-21-00552 manuscript: topologies, initial coordinates and indices, simulation parameters, downsampled trajectories, raw results (RMSD, RMSF).Abstract:The coronaviral pandemic is exerting a tremendously detrimental impact on globalhealth. The Spike proteins of coronaviruses, responsible for cell receptor binding andviral internalization, possess multiple and frequently conservative disulfide bondsraising the question about their role in the antigen function. Here, we present a detailedstructural and functional investigation of the disulfide bonds of the SARS-CoV-2 Spikereceptor-binding domain (RBD). Molecular dynamics simulations of the RBD predictincreased domain flexibility when the four disulfide bonds of the domain are reduced.This flexibility is particularly prominent for the S-S bond-containing surface loop(residues 456-490) that participates in the formation of the interaction surface with theSpike cell receptor ACE2. In vitro the disulfide bond reducing agents affect the RBDsecondary structure, lower its melting temperature from 52°C to 36-39°C and decreaseits binding affinity to ACE2 by two orders of magnitude at 37°C. Consistent with thesein vitro findings, the reducing agents tris (2-carboxyethyl)phosphine (TCEP) anddithiothreitol (DTT) were able to inhibit viral replication at low mM levels in cell-basedassays. Our research demonstrates the mechanism by which the disulfide bonds arecontributing to the molecular structure of the Spike protein, allowing the latter toexecute its viral function.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV