The SARS-CoV-2 Spike Variant D614G Favors an Open Conformational State

Area of Science:

• Virology
• Structural Biology
• Biophysics

Background:

• The emergence of SARS-CoV-2 variants, such as the D614G substitution in the Spike protein, has significantly impacted the COVID-19 pandemic.
• The G-form variant exhibits increased in vitro infectivity and higher viral loads in infected individuals compared to the original D-form.

Approach:

• Utilized microsecond all-atom simulations with multiple replicas to investigate the molecular impact of the D614G substitution on SARS-CoV-2 Spike protein dynamics.
• Focused on the closed and open conformational states of the Spike protein, particularly the open state crucial for binding to the human ACE2 receptor.

Key Points:

• The D614G substitution alters inter-protomer energetics, favoring a higher population of infection-capable (open) Spike protein states.
• In the D-form's open state, inter-protomer interactions between S1 and S2 subunits are asymmetric, a feature resolved in the G-form due to released tensile hydrogen bonds.
• This resolution increases the population of open conformations, suggesting enhanced binding affinity to the ACE2 receptor.

Conclusions:

• The increased infectivity of the D614G SARS-CoV-2 variant is attributed to a higher rate of effective binding encounters with the host ACE2 receptor.
• The G-form variant is predicted to be more sensitive to neutralization, as the substitution enhances the exposure of the receptor-binding domain, a primary target for neutralizing antibodies.