Abstract
Recent experimental evidence demonstrated the capability of SARS-CoV-2 Spike protein to bind sialic acid molecules, which was a trait not present in SARS-CoV and could shed light on the molecular mechanism used by the virus for the cell invasion. This peculiar feature has been successfully predicted by in-silico studies comparing the sequence and structural characteristics that SARS-CoV-2 shares with other sialic acid-binding viruses, like MERS-CoV. Even if the region of the binding has been identified in the N-terminal domain of Spike protein, so far no comprehensive analyses have been carried out on the spike-sialic acid conformations once in the complex. Here, we addressed this aspect performing an extensive molecular dynamics simulation of a system composed of the N-terminal domain of the spike protein and a sialic acid molecule. We observed several short-lived binding events, reconnecting to the avidic nature of the binding, interestingly occurring in the surface Spike region where several insertions are present with respect to the SARS-CoV sequence. Characterizing the bound configurations via a clustering analysis on the Principal Component of the motion, we identified different possible binding conformations and discussed their dynamic and structural properties. In particular, we analyze the correlated motion between the binding residues and the binding effect on the stability of atomic fluctuation, thus proposing regions with high binding propensity with sialic acid.
Highlights
The epidemic of Severe Acute Respiratory Syndrome (SARS)-CoV-2, a novel strain of β-coronavirus first documented in late 2019 [1, 2], has rapidly become pandemic
To investigate protein-ligand interactions at the atomic level, molecular dynamics simulation (MD) with explicit solvent is a powerful computational approach because it allows us to take into account the exploration of the conformational space, as well as the solvent and entropic effects in a physically consistent manner [29], which are weakly considered in standard docking approaches
We studied the binding between spike protein of the SARS-CoV-2 and the sialic acid molecule through an extensive and completely unbiased MD simulation, intending to observe a spontaneous binding between the ligand and the protein
Summary
The epidemic of SARS-CoV-2, a novel strain of β-coronavirus first documented in late 2019 [1, 2], has rapidly become pandemic. We present a computational structural biology study based on extensive molecular dynamics simulation aimed to further investigate the binding between SARS-CoV-2 Spike Nterminal domain (NTD) and a sialic acid molecule, in order to blindly highlight the spike region most prone to interact with glycans. We identified 5 binding modes occurring between these two molecules, involving five possible regions on the NTD, and we investigated if the presence of the glycan stabilize such regions These results shed light on this important molecular interaction, that could provide an additional cell invasion mechanism to the virus possibly explaining the impressive rate of infection showed by SARS-CoV-2
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