First complete coronavirus model shows Spike Proteins in liaison

The COVID-19 virus holds some mysteries. Scientists remain in the dark on aspects of how it fuses and enters the host cell; how it assembles itself; and how it buds off the host cell. Computational modeling combined with experimental data provides insights into these behaviors. But modeling over meaningful timescales of the pandemic-causing SARS-CoV-2 virus has so far been limited to just its pieces like the spike protein, a target for the current round of vaccines.

A new multiscale coarse-grained model of the complete SARS-CoV-2 virion, its core genetic material and virion shell, has been developed for the first time using supercomputers. The model offers scientists the potential for new ways to exploit the virus’s vulnerabilities.

“We wanted to understand how SARS-CoV-2 works holistically as a whole particle,” said Gregory Voth, the Haig P. Papazian Distinguished Service Professor at the University of Chicago. Voth is the corresponding author of the study that developed the first whole virus model, published in the Biophysical Journal. The research team developed a bottom-up coarse-grained model where they took information from atomistic-level molecular dynamics simulations and from experiments. The researchers explained that a coarse-grained model resolves only groups of atoms, versus all-atom simulations, where every single atomic interaction is resolved.  The early results of the study show how the spike proteins on the surface of the virus move cooperatively. Indeed the protein  don’t move independently like a bunch of random, uncorrelated motions, they work together.

This cooperative motion of the spike proteins is informative of how the coronavirus explores and detects the ACE2 receptors of a potential host cell. The results shows the beginnings of how the modes of motion in the spike proteins are correlated. Moreover, it shows the spikes are coupled to each other. When one protein moves another one also moves in response.

The ultimate goal of the model would be, as a first step, to study the initial virion attractions and interactions with ACE2 receptors on cells and to understand the origins of that attraction and how those proteins work together to go on to the virus fusion process.

Professor Voth and his research group have been developing coarse-grained modeling methods on viruses such as HIV and influenza for more than 20 years. They ‘coarsen’ the data to make it simpler and more computationally tractable, while staying true to the dynamics of the system. “The benefit of the coarse-grained model is that it can be hundreds to thousands of times more computationally efficient than the all-atom model. The computational savings allowed the authors to build a much larger model of the coronavirus than ever before, at longer time-scales than what has been done with all-atom models.

The holistic model developed by the authors started with atomic models of the four main structural elements of the SARS-CoV-2 virion: the spike, membrane, nucleocapsid, and envelope proteins. These atomic models were then simulated and simplified to generate the complete course-grained model. The all-atom molecular dynamics simulations of the spike protein component of the virion system, about 1.7 million atoms, were generated . Their model basically ingests our data, and it can learn from the data that we have at these more detailed scales and then go beyond where we went. The method developed will allow  simulation over the longer time scales that are needed to actually simulate the virus infecting a cell. What the authors saw very clearly was the beginning of the dissociation of the S1 subunit of the spike. The whole top part of the spike peels off during fusion. This is one of the first steps of viral fusion with the host cell is this dissociation, where it binds to the ACE2 receptor of the host cell.

The larger S1 opening movements that they saw with this coarse-grained model was something we hadn’t seen yet in the all-atom molecular dynamics, and in fact it would be very difficult for us to see. It’s a critical part of the function of this protein and the infection process with the host cell. That was an interesting finding. The authors used the all-atom dynamical information on the open and closed states of the spike protein generated by the Amaro Lab on the Frontera supercomputer, as well as other data. The National Science Foundation (NSF)-funded Frontera system is operated by the Texas Advanced Computing Center (TACC) at The University of Texas at Austin.

Frontera has shown how important it is for these studies of the virus, at multiple scales. It was critical at the atomic level to understand the underlying dynamics of the spike with all of its atoms. There’s still a lot to learn there. But now this information can be used a second time to develop new methods that allow us to go out longer and farther, like the coarse-graining method. Frontera has been especially useful in providing the molecular dynamics data at the atomistic level for feeding into this model.

One thing that the world is concerned about right now are the UK and the South African SARS-CoV-2 variants. Presumably, with a computational platform like what the authors developed, one can rapidly assess those variances, which are changes of the amino acids. We can hopefully rather quickly understand the changes these mutations cause to the virus and then hopefully help in the design of new modified vaccines going forward.