Potential Pathogenicity Determinants Identified from Structural Proteomics of SARS-CoV and SARS-CoV-2

Abstract

Despite SARS-CoV and SARS-CoV-2 being equipped with highly similar protein arsenals, the corresponding zoonoses have spread among humans at extremely different rates. The specific characteristics of these viruses that led to such distinct outcomes remain unclear. Here, we apply proteome-wide comparative structural analysis aiming to identify the unique molecular elements in the SARS-CoV-2 proteome that may explain the differing consequences. By combining protein modeling and molecular dynamics simulations, we suggest non-conservative substitutions in functional regions of the spike glycoprotein (S), nsp1, and nsp3 that are contributing to differences in virulence. Particularly, we explain why the substitutions at the receptor-binding domain of S affect the structure-dynamics behavior in complexes with putative host receptors. Conservation of functional protein regions within the two taxa is also noteworthy. We suggest that the highly conserved main protease, nsp5, of SARS-CoV and SARS-CoV-2 is part of their mechanism of circumventing the host interferon antiviral response. Overall, most substitutions occur on the protein surfaces and may be modulating their antigenic properties and interactions with other macromolecules. Our results imply that the striking difference in the pervasiveness of SARS-CoV-2 and SARS-CoV among humans seems to significantly derive from molecular features that modulate the efficiency of viral particles in entering the host cells and blocking the host immune response.

SARS-CoV-2 main protease suppresses type I interferon production by preventing nuclear translocation of phosphorylated IRF3

“…To this end, a sensitive activity assay for NSP5 [41], structural determination of NSP5 [42] and proteomic identification of cellular protein substrates of NSP5 [43] are pre-requisites for further research and development efforts. Molecular docking [44], in silico prediction [45] and compound library screening might also prove useful. Our findings on the type I IFN antagonism of NSP5 raise the possibility that NSP5 inhibitors might sensitize infected cells to the antiviral activity of type I IFNs, providing the rationale for combination therapy using type I IFNs and NSP5 inhibitors.…”

Potentially adaptive SARS-CoV-2 mutations discovered with novel spatiotemporal and explainable AI models

“…Once infection is established in the host cell, the viral RNA is replicated and translated, producing 16 nonstructural proteins (nsp1-nsp16) and at least seven auxiliary proteins (ORFs). The overall function of most of these proteins for production of virus is well known (Table 1), and the knowledge gained during the 2002-2004 severe acute respiratory syndrome (SARS) outbreak can add refinements given the high similarity between SARS-CoV-2 and SARS-CoV [8]. Meanwhile, unprecedented efforts of the scientific community have been directed to identify the unique biological features of SARS-CoV-2 leading to the worldwide spread of COVID-19.…”

“…Experimentally solved structures were used in our analyses whenever available. For those not available, we used the models released at https://compsysbio.ornl.gov/covid-1 9/covid-19-structome/, which were predicted with an ensemble workflow of methods [8]. Among those, there are nsp2, the nucleic acid-binding domain of nsp3, and nsp13 structures.…”

Rapid expansion of SARS-CoV-2 variants of concern is a result of adaptive epistasis

“…Here, we processed more than 900,000 SARS-CoV-2 genomes using a computational workflow that combines MJN and protein structural analysis Prates et al 2020) to identify critical attributes of these VOC and provide substantial evidence that the genome-wide mutation load of the late 2020 VOC results from recombination between divergent strains. Via focused structural analysis and molecular dynamics simulations, we explore the individual effects of key mutations in S and other proteins of SARS-CoV-2 that are shared among different VOC.…”