Micro-second time-resolved X-ray single-molecule internal motions of SARS-CoV-2 spike variants

Area of Science:

• Structural Biology
• Virology
• Biophysics

Background:

• SARS-CoV-2 variants like Alpha, Delta, and Omicron exhibit different transmissibility and severity.
• Understanding the molecular dynamics of the spike protein is crucial for comprehending viral entry and evolution.

Purpose of the Study:

• To measure and compare single-molecule intramolecular dynamics of Alpha, Delta, and Omicron SARS-CoV-2 spike proteins.
• To investigate the effect of ACE2 receptor binding on spike protein molecular dynamics.

Main Methods:

• Utilized X-ray techniques for single-molecule measurements.
• Achieved a time resolution of 100 microseconds.
• Analyzed 3-D intramolecular movements and diffusion constants.

Main Results:

• Omicron variant displayed the largest 3-D intramolecular movement, independent of ACE2 binding.
• Intramolecular motion patterns differed significantly between variants with and without ACE2 binding.
• Molecular dynamics of the Omicron spike protein increased upon ACE2 binding, with diffusion constant rising from 71.0 to 91.1 mrad²/ms.

Conclusions:

• SARS-CoV-2 variants possess unique intramolecular dynamics.
• ACE2 receptor binding significantly alters spike protein dynamics, particularly for the Omicron variant.
• These findings provide insights into the structural basis of variant infectivity and potential therapeutic targets.