Large-scale atomic-level supercomputer simulations show that the dominant G-form variant of the virus causing COVID-19 is more infectious in part due to its greater ability to easily bind to its target host receptor in the body, compared to other variants. These research findings from a team led by the Los Alamos National Laboratory shed light on the mechanism of both form G infection and resistance to antibodies against it, which may aid in the future development of a vaccine.
“We have found that the interactions between the basic building blocks of the Spike protein become more symmetrical in the G form, which gives it more opportunities to bind to receptors in the host – in us,” said Gnana. Gnanakaran, corresponding author of the article published today in Scientific advances. “But at the same time, it means that the antibodies can neutralize it more easily. Essentially, the variant stands tall to bind to the receptor, which gives the antibodies a chance to attack it.”
The researchers knew the variant, also known as D614G, was more infectious and could be neutralized by antibodies, but they didn’t know how. Simulating more than a million individual atoms and requiring approximately 24 million CPU hours of supercomputer time, the new work provides molecular-level detail on the behavior of the Spike of this variant.
Current vaccines for SARS-CoV-2, the virus that causes COVID-19, are based on the original D614 form of the virus. This new understanding of Variant G – the most extensive supercomputer simulations of Form G at the atomic level – could mean that it offers a backbone for future vaccines.
The team discovered the D614G variant in early 2020, as the COVID-19 pandemic caused by the SARS-CoV-2 virus increased. These results have been published in Cell. Scientists had observed a mutation in the Spike protein. (In all variants, it is the Spike protein that gives the virus its characteristic crown.) This D614G mutation, named for the amino acid at position 614 on the genome of SARS-CoV-2 which has undergone a substitution of l Aspartic acid, prevailed overall in a matter of weeks.
Spike proteins bind to a specific receptor found in many of our cells via the Spike receptor binding domain, ultimately leading to infection. This binding requires the receptor binding domain to change structurally from a closed conformation, which cannot bind, to an open conformation, which can.
Simulations from this new research demonstrate that the interactions between the building blocks of the Spike are more symmetrical in the new G-form variant than those in the original D strain. This symmetry leads to more viral spikes in the open conformation, so that it can more easily infect a person.
A team of Los Alamos postdoctoral fellows – Rachael A. Mansbach (now assistant professor of physics at Concordia University), Srirupa Chakraborty and Kien Nguyen – led the study by running multiple microsecond scale simulations of the two variants in both conformations. of the receptor binding domain to shed light on how the Spike protein interacts with both the host’s receptor and with neutralizing antibodies that may help protect the host against infection. Members of the research team also included Bette Korber from Los Alamos National Laboratory and David C. Montefiori, Duke Human Vaccine Institute.
The team would like to thank Paul Weber, head of institutional IT at Los Alamos, for providing access to the laboratory’s supercomputers for this research.
The paper: “The D614G variant of SARS-CoV-2 Spike promotes an open conformational state,” Scientific progress. Rachael A. Mansbach, Srirupa Chakraborty, Kien Nguyen, David C. Montefiori, Bette Korber, S. Gnanakaran.
Funding: The project was supported by the Los Alamos Lab led research and development project 20200706ER, the Director’s Postdoctoral Fellowship, and the Los Alamos Center for Nonlinear Studies Postdoctoral Program.