Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein

Area of Science:

• Structural biology and virology
• Coronaviridae protein dynamics

Background:

• The SARS-CoV-2 spike glycoprotein is crucial for viral entry, mediating ACE2 receptor binding and membrane fusion.
• Spike protein exists in dynamic conformations (closed and open), influencing receptor binding and immune evasion.
• Variants of Concern (VOCs) exhibit mutations enhancing virulence and immune escape.

Purpose of the Study:

• To investigate dynamic changes in the SARS-CoV-2 spike protein associated with conformational transitions, ACE2 binding, and VOC mutations.
• To understand the structural basis of immune evasion in VOCs, particularly Omicron.

Main Methods:

• Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) was employed to analyze spike protein dynamics.
• Conformational changes were studied in relation to ACE2 binding and specific mutations found in VOCs.

Main Results:

• The RBD-associated subdomain influences spike opening, while the NTD is a key region for VOC conformational divergence and immune evasion.
• Alpha, Beta, and Delta variants predominantly adopt open conformations, with ACE2 binding priming spikes for fusion.
• Omicron variant spikes maintain predominantly closed conformations, facilitating antibody escape, yet exhibit pre-primed fusion characteristics.

Conclusions:

• Spike protein dynamics are critical for SARS-CoV-2 infectivity and evolution.
• Distinct conformational dynamics in VOCs, especially Omicron, explain their increased transmissibility and immune evasion.
• Findings provide insights into SARS-CoV-2 evolution and the emergence of immune-evasive variants.