Conformational flexibility and structural variability of SARS-CoV2 S protein

Area of Science:

• Structural biology
• Virology
• Immunology

Background:

• The SARS-CoV-2 spike (S) glycoprotein is crucial for viral entry.
• Understanding S protein conformations at different pH levels is vital for vaccine development.
• Previous studies primarily focused on pH 8.0, limiting knowledge of physiological conditions.

Purpose of the Study:

• To investigate the conformational states of the SARS-CoV-2 S protein at physiological and near-physiological pH.
• To determine the pH-dependent conformational propensities of the S protein.
• To identify structural dynamics and exposed epitopes relevant for therapeutic strategies.

Main Methods:

• Single-particle cryoelectron microscopy (cryo-EM) was utilized.
• Visualized S protein conformations at pH 7.4, 6.5, and 8.0.
• Analyzed conformational dynamics across N-terminal, RBD, S2, and stalk domains.

Main Results:

• The S protein exhibits distinct open and closed conformations.
• Conformational propensities vary significantly with pH.
• At pH 7.4, approximately 68% of the S protein was observed in an open conformation.
• Continuous movements were noted in key domains (NTD, RBD, S2, stalk) across different pH values.
• Key residues within RBD-neutralizing epitopes showed differential exposure based on conformation and pH.

Conclusions:

• pH significantly influences SARS-CoV-2 S protein conformation and dynamics.
• The prevalence of the open conformation at physiological pH (7.4) has implications for viral entry and immune response.
• Findings provide structural insights crucial for designing effective vaccines and therapeutics targeting SARS-CoV-2.