Glycan shields allow viruses to hide from their host’s immune system. In SARS-CoV-2, however, it seems that they may also play a critical role in gaining access to the cell, without which the virus would be rendered harmless. Elisa Fadda of Maynooth University has been using molecular dynamics simulations to examine these complex carbohydrates in more detail.
Complex carbohydrates are the most abundant biomolecules in the natural world. Most proteins are covered in a thin layer of these branched structures, which can be made up of any number of hundreds of different units. However, despite their ubiquity, they have historically been almost entirely disregarded when considering the structure of the molecules they are attached to, seen as unnecessary details that do not contribute to the overall function.
Massive progress in the field of complex carbohydrate research over the past 20 years has now changed the perception of these molecules from that of redundant decorations to essential biological enablers. As it turns out, the fine layer that they form around proteins, like moss on a stone, often plays a crucial role in the protein’s function – including that of the SARS-CoV-2 spike protein.
Understanding how these carbohydrates behave is a tricky process. They are highly dynamic and highly flexible, meaning that most traditional experimental methods are unable to capture any useful information about their function. Instead, computational biophysicists like Elisa Fadda of Maynooth University painstakingly reconstruct these biomolecules digitally so that they can see how they move and react in their own environment.
The famous spike protein that allows SARS-CoV-2 to attach to our cells has been studied in great detail over the past year by researchers looking for ways to target it in the treatment of COVID-19. Studying the carbohydrates that cover the surface of the protein is essential for understanding the disease better, as Fadda explains. “Working alongside my colleague Rommie Amaro in San Diego, we have shown that SARS-CoV-2 is entirely unique from other viruses due to what is known as its glycan shield.” This coat of carbohydrates that hides the virus from our immune system is present in all enveloped viruses, including HIV and influenza.
“What makes it unique in this coronavirus is that specific glycans within the shield are intrinsically involved in the mechanism of the spike protein that allows it to latch on to our cells. Without these glycans, the spike protein would be useless and the virus would not be contagious or dangerous in any way.”
Graphical representation of the SARS-CoV-2 virus surface (grey) with the spike (S) proteins highlighted in blue. The atomistic model of the fully-glycosylated SARS-CoV-2 S embedded in the viral membrane is shown on the right-hand side.
Image source: Courtesy of Dr. L. Casalino, Amaro Lab, UCSD. Reference: Casalino et al., ACS Central Sci (2020), DOI: 10.1021/acscentsci.0c01056.
This feature of SARS-CoV-2 could explain another unusual phenomenon that it displays. Viruses replicate by hijacking the cellular machinery of their host. As such, the glycan shield of SARS-CoV-2 is made by whatever cell its predecessor infected. Where this becomes interesting is that the different types of cells in our body – cells in our lungs, cells in our intestine – produce different glycan shields. This leads to variation in the infectivity of the virus depending on what type of cell it has come from.
Analysing this viral quirk experimentally is an almost impossible task. However, Fadda and her colleagues have been able to construct various types of glycan shields and use high performance computers to see how they behave. This could pave the way for some new therapeutic approaches. “It’s possible that instead of targeting the spike protein, the glycosylation machinery that creates the glycan coats could be hindered in some way so that any viruses created would have defective spikes.
“Of course, any therapy targeting this would have to be very selective as 70% of the proteins we create in our body are glycosylated. It will probably be a case of refining the strategy so one or two enzymes are being targeted.”
Snapshot captured from one of the MD trajectories of one of the SARS-CoV-2 S models studied in Casalino et al. (2020) illustrates how the glycans highlighted around the open receptor-binding domain (RBD) support its open/active conformation, affecting its binding to the angiotensin converting enzyme 2 (ACE2) primary receptor. Ongoing work in Dr. Fadda’s lab funded by PRACE is aimed at invesitigating if and how different glycoforms can modulate this function of the SARS-CoV-2 glycan shield.
Fadda’s studies on the role that glycosylation plays in SARS-CoV-2 have partially been made possible by a PRACE allocation of 15.84 million core hours on the Marconi100 supercomputer. Using molecular dynamics simulations, her team has studied five spike protein models with different patterns of glycosylation, observing how the carbohydrates react and rearrange as the spike binds to a human cell. “These simulations allow us to see the whole system moving and show us the role that the carbohydrates play,” says Fadda. “It’s like using a computational microscope that provides detail down to the level of atoms in real time.”
With data collection continuing until the end of November 2020, a paper on the work carried out in the PRACE project will likely be published in December. The project builds upon work carried out earlier this year on the NSF Frontera computing system at the Texas Advanced Computing Center. The unique perspective that Fadda’s work provides, along with the extremely high-profile nature of the COVID-19 pandemic, also led to her work featuring in the New York Times in early October.*
“The whole experience of continuing our work on this with PRACE has been fabulous,” she says. “We were able to access our allocation straight away and, when we needed help, it was available immediately.”
* See the Success Story on the work of Gerhard Hummer that features in the New York Times article as well.
This article was also published in PRACE Digest 2020.
15.84 million cumulative core hours (i.e 45 000 node hours) on Marconi100 hosted by CINECA, Italy
L. Casalino, Z. Gaieb, J.A. Goldsmith, C.K. Hjorth, A.C. Dommer, A.M. Harbison, C.A. Fogarty, E.P. Barros, B.C. Taylor, J.S. McLellan, E. Fadda and R.E. Amaro. Beyond Shielding: The Roles of Glycans in the SARS-CoV-2 Spike Protein, ACS Central Science (2020) 6 (10), 1722-173, DOI: 10.1021/acscentsci.0c01056