Structural impact on SARS-CoV-2 spike protein by D614G substitution
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Updated: Nov 12, 2025

Engineering Antiviral Agents via Surface Plasmon Resonance
Published on: June 14, 2022
Jun Zhang1,2, Yongfei Cai1,2, Tianshu Xiao1,2
1Division of Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Abstract:
Substitution for aspartic acid (D) by glycine (G) at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. Here, we report cryo-electron microscopy structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations that differ primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer-effectively increasing the number of functional spikes and enhancing infectivity-and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.
Insights
The G614 variant of SARS-CoV-2 spike protein enhances viral spread and infectivity. Structural analysis reveals a stabilizing loop interaction in the G614 spike, improving vaccine immunogen design.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- The G614 substitution in the SARS-CoV-2 spike protein is associated with increased viral transmissibility.
- Understanding the structural basis of G614's enhanced infectivity is crucial for developing effective vaccines and therapeutics.
Purpose of the Study:
- To determine the cryo-electron microscopy structures of the full-length G614 spike protein trimer.
- To elucidate the structural differences between the D614 and G614 spike proteins and their functional implications.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to resolve the structures of the G614 spike trimer.
- Comparative structural analysis was performed between D614 and G614 spike protein conformations.
Main Results:
- The G614 spike trimer adopts three distinct prefusion conformations, differing in receptor-binding domain positioning.
- A novel loop interaction in the G614 spike stabilizes the trimer, increasing functional spikes and infectivity.
- This stabilization modulates structural rearrangements essential for viral membrane fusion.
Conclusions:
- The G614 substitution enhances SARS-CoV-2 infectivity through increased trimer stability.
- Structural insights into the G614 spike protein can inform the design of improved immunogens for vaccine development.
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