Predicting the future of COVID – Boston College Chronicle

The spike protein of the coronavirus, or SARS-CoV-2, binds to a receptor on the host cells, called ACE2, which allows the virus to enter the cells and infect it. Binding is the first step for infection, and several mutations in previous variants of concern have been shown to be important for increasing the spike's binding to human ACE2.

We use a fully quantum mechanical model to theoretically assess how different mutations in the spike can contribute to its increased, or decreased, binding strength to human ACE2, Momeni said. The modeling shows that Omicron binds to receptor proteins stronger than the currently dominant Delta variant.

In addition to Momeni, Boston College Professor of Biology Welkin Johnson and post-doctoral researcher Marco Zaccaria, Luigi Genovese of French CEA - University of Grenoble Alpes, and Professor Michael Farzan of the Scripps Research Institute, contributed to the report"Investigating the mutational landscape of the SARS-CoV-2 Omicron variant viaab initioquantum mechanical modeling,which is available at the pre-print host site bioRxiv.

We find that Omicron has not reached its full potential to bind human host cells, Momeni said. We identify mutations that can strengthen the virus affinity for the human cell, which could increase infectivity and evasion of antibodies. He cautioned that increased infectivity is only one important aspect in variants of concern; it is also important to monitor the severity of symptoms and the ability of the variant to evade antibodies and vaccines.

While the study found that Omicrons spike proteins bind better than the Delta variant to the human ACE2 receptor, not all mutations in the spike proteins targeting systemknown as a receptor binding domainare beneficial for binding, which suggests factors other than binding may also be involved in determining how the variant evolves.

One possible explanation is that the variant has acquired mutations to evade host antibodies, Momeni said. Such mutations can be detrimental to its binding to the host receptor and were followed by additional compensatory mutations to recover, or even improve, its receptor binding.

Momeni said the team was surprised to see a range of mutationssome beneficial, some neutral, and some detrimentalto hACE2 binding. He said the teams next steps are to experimentally validate the predictions of the model.

The teams findings on Omicron build upon a prior analysis of the Wuhan and Delta variants by the team. There, modeling found that E484 was actually a weak link in the original Wuhan strain, but it has evolved through mutation to better bind to human host cells and to evade some antibodies, Momeni said. Additionally, the team found that the Wuhan strain bindingto ACE2 in bats was more optimized than the human counterpart. The team predicted further E484K mutation added to the Delta variant would produce a future variant of concern.

Ed Hayward | University Communications | December 2021

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Predicting the future of COVID - Boston College Chronicle