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Dynamic View of Spike Protein Reveals Prime Targets for COVID-19 Treatments

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SARS-CoV-2’s spike protein showing attached glycans and regions for antibody binding.
Credit: Sikora M, PLoS Comput Biol, 2021

This striking portrait features the spike protein that crowns SARS-CoV-2, the coronavirus that causes COVID-19. This highly flexible protein has settled here into one of its many possible conformations during the process of docking onto a human cell before infecting it.

This portrait, however, isn’t painted on canvas. It was created on a computer screen from sophisticated 3D simulations of the spike protein in action. The aim was to map its many shape-shifting maneuvers accurately at the atomic level in hopes of detecting exploitable structural vulnerabilities to thwart the virus.

For example, notice the many chain-like structures (green) that adorn the protein’s surface (white). They are sugar molecules called glycans that are thought to shield the spike protein by sweeping away antibodies. Also notice areas (purple) that the simulation identified as the most-attractive targets for antibodies, based on their apparent lack of protection by those glycans.

This work, published recently in the journal PLoS Computational Biology [1], was performed by a German research team that included Mateusz Sikora, Max Planck Institute of Biophysics, Frankfurt. The researchers used a computer application called molecular dynamics (MD) simulation to power up and model the conformational changes in the spike protein on a time scale of a few microseconds. (A microsecond is 0.000001 second.)

The new simulations suggest that glycans act as a dynamic shield on the spike protein. They liken them to windshield wipers on a car. Rather than being fixed in space, those glycans sweep back and forth to protect more of the protein surface than initially meets the eye.

But just as wipers miss spots on a windshield that lie beyond their tips, glycans also miss spots of the protein just beyond their reach. It’s those spots that the researchers suggest might be prime targets on the spike protein that are especially promising for the design of future vaccines and therapeutic antibodies.

This same approach can now be applied to identifying weak spots in the coronavirus’s armor. It also may help researchers understand more fully the implications of newly emerging SARS-CoV-2 variants. The hope is that by capturing this devastating virus and its most critical proteins in action, we can continue to develop and improve upon vaccines and therapeutics.

Reference:

[1] Computational epitope map of SARS-CoV-2 spike protein. Sikora M, von Bülow S, Blanc FEC, Gecht M, Covino R, Hummer G. PLoS Comput Biol. 2021 Apr 1;17(4):e1008790.

Links:

COVID-19 Research (NIH)

Mateusz Sikora (Max Planck Institute of Biophysics, Frankfurt, Germany)

The surprising properties of the coronavirus envelope (Interview with Mateusz Sikora), Scilog, November 16, 2020.


How COVID-19 Took Hold in North America and Europe

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SARS-CoV-2 Tracking
Caption: SARS-CoV-2 introductions to U.S. and Europe. Credit: Modified from Worobey M, Science, 2020.

It was nearly 10 months ago on January 15 that a traveler returned home to the Seattle area after visiting family in Wuhan, China. A few days later, he started feeling poorly and became the first laboratory-confirmed case of coronavirus disease 2019 (COVID-19) in the United States. The rest is history.

However, new evidence published in the journal Science suggests that this first COVID-19 case on the West Coast didn’t snowball into the current epidemic. Instead, while public health officials in Washington state worked tirelessly and ultimately succeeded in containing its sustained transmission, the novel coronavirus slipped in via another individual about two weeks later, around the beginning of February.

COVID-19 is caused by the novel coronavirus SARS-CoV-2. Last winter, researchers sequenced the genetic material from the SARS-CoV-2 that was isolated from the returned Seattle traveler. While contact tracing didn’t identify any spread of this particular virus, dubbed WA1, questions arose when a genetically similar virus known as WA2 turned up in Washington state. Not long after, WA2-like viruses then appeared in California; British Columbia, Canada; and eventually 3,000 miles away in Connecticut. By mid-March, this WA2 cluster accounted for the vast majority—85 percent—of the cases in Washington state.

But was it possible that the WA2 cluster is a direct descendent of WA1? Did WA1 cause an unnoticed chain of transmission over several weeks, making the Seattle the epicenter of the outbreak in North America?

To answer those questions and others from around the globe, Michael Worobey, University of Arizona, Tucson, and his colleagues drew on multiple sources of information. These included data peretaining to viral genomes, airline passenger flow, and disease incidence in China’s Hubei Province and other places that likely would have influenced the probability that infected travelers were moving the virus around the globe. Based on all the evidence, the researchers simulated the outbreak more than 1,000 times on a computer over a two-month period, beginning on January 15 and assuming the epidemic started with WA1. And, not once did any of their simulated outbreaks match up to the actual genome data.

Those findings suggest to the researchers that the idea WA1 is responsible for all that came later is exceedingly unlikely. The evidence and simulations also appear to rule out the notion that the earliest cases in Washington state entered the United States by way of Canada. A deep dive into the data suggests a more likely scenario is that the outbreak was set off by one or more introductions of genetically similar viruses from China to the West Coast. Though we still don’t know exactly where, the Seattle area is the most likely site given the large number of WA2-like viruses sampled there.

Worobey’s team conducted a second analysis of the outbreak in Europe, and those simulations paint a similar picture to the one in the United States. The researchers conclude that the first known case of COVID-19 in Europe, arriving in Germany on January 20, led to a relatively small number of cases before being stamped out by aggressive testing and contact tracing efforts. That small, early outbreak probably didn’t spark the later one in Northern Italy, which eventually spread to the United States.

Their findings also show that the chain of transmission from China to Italy to New York City sparked outbreaks on the East Coast slightly later in February than those that spread from China directly to Washington state. It confirms that the Seattle outbreak was indeed the first, predating others on the East Coast and in California.

The findings in this report are yet another reminder of the value of integrating genome surveillance together with other sources of data when it comes to understanding, tracking, and containing the spread of COVID-19. They also show that swift and decisive public health measures to contain the virus worked when SARS-CoV-2 first entered the United States and Europe, and can now serve as models of containment.

Since the suffering and death from this pandemic continues in the United States, this historical reconstruction from early in 2020 is one more reminder that all of us have the opportunity and the responsibility to try to limit further spread. Wear your mask when you are outside the home; maintain physical distancing; wash your hands frequently; and don’t congregate indoors, where the risks are greatest. These lessons will enable us to better anticipate, prevent, and respond to additional outbreaks of COVID-19 or any other novel viruses that may arise in the future.

Reference:

[1] The emergence of SARS-CoV-2 in Europe and North America. Worobey M, Pekar J, Larsen BB, Nelson MI, Hill V, Joy JB, Rambaut A, Suchard MA, Wertheim JO, Lemey P. Science. 2020 Sep 10:eabc8169 [Epub ahead of print]

Links:

Coronavirus (COVID-19) (NIH)

Michael Worobey (University of Arizona, Tucson)

NIH Support: National Institute of Allergy and Infectious Diseases; Fogarty International Center; National Library of Medicine