The SARS-CoV-2 variants that have emerged in the past few months have attracted an immense amount of speculation. Specifically, whether the mutations may confer an advantage to the virus, render our antibodies ineffective, and lead to vaccine escape. New research has uncovered why the G614 strain (with a substitution for aspartic acid by glycine at position 614 in the spike protein) and its recent variants—which are now the dominant circulating forms of the virus—facilitate rapid viral spread.
The work, led by Bing Chen, PhD, at Boston Children’s Hospital, analyzed how the structure of the spike protein changes with the D614G mutation. Using cryo-electron microscopy (cryo-EM), which has resolution down to the atomic level, they report structures of a full-length G614 spike trimer which adopts three distinct prefusion conformations differing primarily by the position of one receptor-binding domain (RBD). Chen’s team found that the D614G mutation makes the spike more stable as compared with the original SARS-CoV-2 virus.
This work is published in Science, in the paper, “Structural impact on SARS-CoV-2 spike protein by D614G substitution.”
In the original coronavirus, the spike proteins would bind to the ACE2 receptor and then dramatically change shape, folding in on themselves. This enabled the virus to fuse its membrane with our own cells’ membranes and get inside. However, as Chen and colleagues reported in July 2020, the spikes would sometimes prematurely change shape and fall apart before the virus could bind to cells. While this slowed the virus down, the shape change also made it harder for our immune system to contain the virus.
“Because the original spike protein would dissociate, it was not good enough to induce a strong neutralizing antibody response,” said Chen.
When Chen and colleagues imaged the mutant spike protein, the authors noted that a loop disordered in the D614 spike trimer wedges between domains within a protomer in the G614 spike. This added interaction, they added, 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.” In short, the more functional spikes are available to bind to cells’ ACE2 receptors, making the virus more infectious.
The researchers found that the D614G mutation stabilizes the spike by blocking the premature shape change. Interestingly, the mutation also makes the spikes bind more weakly to the ACE receptor, but the fact that the spikes are less apt to fall apart prematurely renders the virus overall more infectious.
“Say the original virus has 100 spikes,” Chen explained. “Because of the shape instability, you may have just 50% of them functional. In the G614 variants, you may have 90% that are functional, so even though they don’t bind as well, the chances are greater that you will have infection.”
Chen proposes that redesigned vaccines incorporate the code for this mutant spike protein. The more stable spike shape should make any vaccine based on the spike more likely to elicit protective neutralizing antibodies, he said. Indeed, the Moderna, Pfizer, and Johnson & Johnson vaccines are all based on the spike protein.
Chen and his colleagues are further applying structural biology to better understand how SARS-CoV-2 binds to the ACE2 receptor, with an eye toward therapeutics to block the virus from gaining entry to our cells.
In January, the team showed in Nature Structural & Molecular Biology that a structurally-engineered “decoy” ACE2 protein binds the virus 200 times more strongly than the body’s own ACE2. The decoy potently inhibited the virus in cell culture, suggesting it could be an anti-COVID-19 treatment. Chen is now planning to advance this research into animal models.
