The coronavirus sports a luxurious sugar coat. “It’s striking,” thought Rommie Amaro, staring at her computer simulation of one of the trademark spike proteins of SARS-CoV-2, which stick out from the virus’s surface. It was swathed in sugar molecules, known as glycans.
“When you see it with all the glycans, it’s almost unrecognizable,” says Amaro, a computational biophysical chemist at the University of California, San Diego.
Many viruses have glycans covering their outer proteins, camouflaging them from the human immune system like a wolf in sheep’s clothing. But last year, Amaro’s laboratory group and collaborators created the most detailed visualization yet of this coat, based on structural and genetic data and rendered atom-by-atom by a supercomputer. On 22 March 2020, she posted the simulation to Twitter. Within an hour, one researcher asked in a comment: what was the naked, uncoated loop sticking out of the top of the protein?
Amaro had no idea. But ten minutes later, structural biologist Jason McLellan at the University of Texas at Austin chimed in: the uncoated loop was a receptor binding domain (RBD), one of three sections of the spike that bind to receptors on human cells (see ‘A hidden spike’).
In Amaro’s simulation, when the RBD lifted up above the glycan cloud, two glycans swooped in to lock it into place, like a kickstand on a bicycle. When Amaro mutated the glycans in the computer model, the RBD collapsed. McLellan’s team built a way to try the same experiment in the lab, and by June 2020, the collaborators had reported that mutating the two glycans reduced the ability of the spike protein to bind to a human cell receptor1 — a role that no one has previously recognized in coronaviruses, McLellan says. It’s possible that snipping out those two sugars could reduce the virus’s infectivity, says Amaro, although researchers don’t yet have a way to do this.
Since the start of the COVID-19 pandemic, scientists have been developing a detailed understanding of how SARS-CoV-2 infects cells. By picking apart the infection process, they hope to find better ways to interrupt it through improved treatments and vaccines, and learn why the latest strains, such as the Delta variant, are more transmissible.
What has emerged from 19 months of work, backed by decades of coronavirus research, is a blow-by-blow account of how SARS-CoV-2 invades human cells (see ‘Life cycle of the pandemic coronavirus’). Scientists have discovered key adaptations that help the virus to grab on to human cells with surprising strength and then hide itself once inside. Later, as it leaves cells, SARS-CoV-2 executes a crucial processing step to prepare its particles for infecting even more human cells. These are some of the tools that have enabled the virus to spread so quickly and claim millions of lives. “That’s why it’s so difficult to control,” says Wendy Barclay, a virologist at Imperial College London.
Barbed and ready
It starts with the spikes. Each SARS-CoV-2 virion (virus particle) has an outer surface peppered with 24–40 haphazardly arranged spike proteins that are its key to fusing with human cells2. For other types of virus, such as influenza, external fusion proteins are relatively rigid. SARS-CoV-2 spikes, however, are wildly flexible and hinge at three points, according to work published in August 2020 by biochemist Martin Beck at the Max Planck Institute of Biophysics in Frankfurt, Germany, and his colleagues3.
That allows the spikes to flop around, sway and rotate, which could make it easier for them to scan the cell surface and for multiple spikes to bind to a human cell. There are no similar experimental data for other coronaviruses, but because spike-protein sequences are highly evolutionarily conserved, it is fair to assume the trait is shared, says Beck….
