How D614G Mutation of SARS-CoV-2 Enabled its Rapid Spread

Category Health

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Researchers at RIKEN investigated the effect of mutations on the SARS-CoV-2 virus and found that a single mutation on the Spike Protein changed its shape and enabled it to better spread among humans. The finding could help develop next-generation vaccines and antiviral drugs.

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Molecular modeling suggests structural consequences of an early protein mutation that promoted viral transmission.

RIKEN researchers discovered that an early mutation (D614G) in the SARS-CoV-2 virus may have contributed to its rapid spread by altering the spike protein’s shape, improving the virus’s ability to adapt to human hosts. The finding could help inform the development of next-generation vaccines and antiviral drugs.

The mutation is called the D614G mutation and it affects the shape of the Spike Protein on the SARS-CoV-2.

The rapid spread of COVID-19 may have been partly due to changes in the structure of the SARS-CoV-2 virus wrought by an early mutation in its genome, a detailed analysis by RIKEN researchers suggests. The finding could help inform the development of next-generation vaccines and antiviral drugs.

Alpha, Delta, Omicron, and other variants of concern have been making news throughout the COVID-19 pandemic. But the most significant mutation may have occurred in the early days of the pandemic, and it might have enabled the virus to spread so rapidly.

The Spike Protein helps the virus bind and enter human cells.

Yuji Sugita of the RIKEN Center for Computational Science (R-CCS) and Hisham Dokainish, who was at R-CCS at the time of the study, investigated the effect of mutations on viral structure. They did this by simulating the atomic positions of molecules found in different forms of the virus’s important spike protein—a tool coronaviruses use to bind and enter human cells.

They found that the substitution of a single amino acid altered this protein’s shape, helping SARS-CoV-2 to adapt to human hosts. This finding demonstrates how even tiny mutations—swapping a single amino acid in this case—can greatly affect protein dynamics.

When the protein changed shape due to the mutation, it made it easier for the virus to enter human cells.

To understand why the mutation proved so advantageous to the virus, the pair ran detailed simulations of the protein’s structure and stability. Their analysis—done using the RIKEN Fugaku supercomputer, one of the fastest in the world—revealed how the mutation (known as D614G) breaks an ionic bond with a second subunit of the Spike protein. It also changes the shape of a nearby loop structure, which alters the orientation of the entire protein, locking it into a form that makes it easier for the virus to enter cells (Fig. 1).

The D614G mutation breaks an ionic bond between two subunits of the Spike Protein.

"A single and local change in an interaction within the molecule caused by a single mutation could affect the global structure of the spike protein," explains Sugita, who is additionally affiliated with the RIKEN Center for Biosystems Dynamics Research. The resulting mutant proved better at replicating and transmitting between human hosts, and the D614Glineage quickly outcompeted its ancestral lineages and spread across the globe. It remains a fixture of every dominant variant that has followed.

The mutation locks the protein into a form which is more easy to use to bind and enter cells.

Sugita’s team is now performing similar investigations of adaptive viral mutations that arose later in the course of the pandemic, including those found in the Omicron variant.

"Information obtained from our molecular dynamics simulations should help increase the opportunities for us to find effective drugs and other medicines," he says.

Reference: "Structural effects of spike protein D614G mutation in SARS-CoV-2" by Hisham M. Dokainish and Yuji Sugita, 16 November 2022, Biophysical Journal.DOI: 10.1016/j.bpj.2022.11.025 .

Investigators simulated molecules of the virus’s Spike Protein to determine how much the mutation altered its shape and stability.

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