SARS-CoV-2 entry takes place either at the surface of the host cell membrane at normal pH or at the surface of endocytic vesicles at acidic pH. In these two entry mechanisms,a viral entry glycoprotein located at the surface of the virus (the spike) gets exposed to different environmental conditions: normal pH and low pH. Titratable residues such as Glu or Asp at the surface of the Spike protein could change protonation state at different pHs, which could lead to changes of the protein conformation that consequently modulate viral entry. T. Zhou et al. proposed that the part of the spike called the Fusion Peptide Proximal Region (FPPR) is pH-dependent and they reported seeing two different conformations at two different pHs. However our analysis of all available experimental structures in Protein Data Bank is inconsistent with the conclusions of T. Zhou et al. The inconsistency might come from a scarcity of Spike protein structures that were determined at low pH. To understand if the FPPR conformation depends on pH, and which titratable residues might modulate the conformation change, we performed constant pH replica exchange molecular dynamics simulations. We found that pKas of titratable residues in Fusion Peptide Proximal Region indeed differ between the alternate conformations, supporting the hypothesis of FPPR pH-dependence.

Does low pH influence the conformation of the SARS-CoV-2 spike glycoprotein?

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