The devil in the details of the coronavirus merger


Image: The mechanism by which the coronavirus fuses with host cells has been proposed through simulations by University of Chicago researchers using the Frontera supercomputer at TACC. Representative plot of a coarse-grain (CG) simulation of spike trimers in a membrane interacting with an adjacent membrane containing ACE2 dimers. Insets show the CG model components for the spike trimer (bottom), ACE2 dimer (top left), and lipid membrane (top right).
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Photo credits: Pak, AJ, Yu, A, Ke, Z, et al.

The mystery of how exactly the SARS-CoV-2 virus infects human lung cells remains largely hidden from experimental scientists. Now, however, the devilish details of the mechanism by which the coronavirus fuses with host cells have been suggested by simulations by University of Chicago researchers using the Frontera supercomputer at the Texas Advanced Computing Center (TACC).

The computer models show the cooperative behavior of host cell receptor proteins that lead to their own infection. The work can be applied to understanding the increased virulence of coronavirus variants such as Delta, Omicron and more.

“We discovered that the spike protein interacts very cooperatively with two ACE2 receptors,” said Gregory Voth, a distinguished professor of chemistry at the University of Chicago. “This is a fundamental biophysical finding.”

Voth is the senior author of the study, which modeled the interactions of the coronavirus and receptor cells using computer simulations published in the journal nature communication in February 2022.

Like a spiked soccer ball, the spike proteins adorn the surface of the coronavirus. The spikes seek out and fuse with the angiotensin converting enzyme 2 (ACE2) protein receptors in human lung cells. The spike protein consists of two main parts. The S1 domain contains the receptor binding domain that recognizes ACE2 proteins. And the S2 domain contains the fusion machinery, which is protected and covered like a shell by the S1 domain.

The simulations show how one ACE2 receptor protein holds on to the coronavirus spike and weakens it while the other begins to pull it apart. The S1 domain then falls apart, exposing the fusion machinery. This double whammy primes the virus for fusion and entry into human lung host cells.

“It seems that variants like Delta and Omicron can amplify this behavior – this is a crucial step. Ultimately, future antibodies and possibly molecular pharmaceuticals should be able to disrupt this process,” Voth said.

Voth and colleagues developed what they call “bottom-up coar-grained models” that took cryo-electron tomography data from the lab of study co-author John Briggs of the Max Planck Institute for Biochemistry. They combined it with atomistic molecular dynamics simulations. The data generated fed into a theoretical framework that developed the coarse-grained models.

“The coarse-grained models are up to 1,000 times faster than purely atomistic molecular dynamics simulations, but they retain the essential physical properties,” said Voth. This method offers enormous time and money savings in the calculations.

The science team received supercomputing resources and services from the COVID-19 HPC Consortium, a public-private initiative to support COVID-19 research. Through the consortium, they used the National Science Foundation-funded Frontera system at TACC; the Witherspoon computer cluster at IBM Research; and Oak Ridge Leadership Computing Facility resources at Oak Ridge National Laboratory.

“We calculated molecular dynamics data of all atoms on Frontera and used analysis tools available from TACC – both were very valuable,” said Voth.

Voth’s team submitted their work before the Delta and Omicron variants were known, so they didn’t predict the mutations. But they went back and reworked the models to examine the variants.

“Delta has something like an opening in the spike that occurs more easily than previous coronavirus mutations,” Voth said. “From a scientific perspective, it felt exciting to see behaviors that hadn’t been observed before.”

Voth pointed to cryo-electron microscopy lab data showing the structure of a soluble spike protein with two ACE2 receptors bound to it. But he distinguished this crystallized example from what he was studying with simulations in the more realistic environment of many proteins interacting with each other on membrane sheets.

Voth: “If they are used well and are based on good physics, supercomputers can offer a completely new perspective on these processes. Computer simulation allows you to study things that are currently not possible with experiments. Simulation and experiments work very well.” well together, hand in hand.


The study, “Cooperative multivalent receptor binding promotes exposure of the core of the SARS-CoV-2 fusion machinery” was published in the journal in February 2022 nature communication. The authors of the study are Alvin Yu and Gregory A. Voth of the University of Chicago; Alexander J. Pak of the Colorado School of Mines; Zunlong Ke and John AG Briggs from the Max Planck Institute for Biochemistry. Funding from the National Science Foundation CHE-2029092; the European Research Council ERC-CoG-648432 MEMBRANE EFUSION; the UK Medical Research Council for research and innovation MC_UP_1201/16; the National Institute of Allergy and Infectious Diseases of the National Institutes of Health F32 AI150477 and F32 AI150208; and resources awarded by the COVID-19 HPC Consortium.

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