Sunday , April 18 2021

The first complete coronavirus model shows collaboration

The first complete coronavirus model shows collaboration

Using supercomputers, a multidimensional model of the entire SARS-CoV-2 virion was first developed. The model offers scientists new opportunities to exploit the vulnerability of the virus. Exterior (L) and interior (R) views protein trimmers (thorny), glycosylation sites (black), membrane proteins (blue), and pentameric envelope ion channels (orange). Credit: Gregory Voth, University of Chicago.

The COVID-19 virus hides some secrets. Scientists remain in the dark about aspects of how it merges and enters the host cell; how to put it together; and how it branches off from the host cell.

Computer modeling combined with experimental data provides insight into this behavior. But modeling of important time frames of the pandemic-causing SARS-CoV-2 virus has so far been limited to only bits of it, such as spike protein, the target of the current vaccine cycle.

Using supercomputers, a new multi-month coarse-grained model of the entire SARS-CoV-2 virion, whose basic genetic material and virion shell, was developed for the first time. The model offers scientists new opportunities to exploit the vulnerability of the virus.

“We wanted to understand how SARS-CoV-2 works holistically as a whole,” said Gregory Voth, Professor Emeritus Haig P. Papazian at the University of Chicago. Voth is the relevant author of a study that developed the first complete model of the virus, published in November 2020 in Biophysical Journal.

“We developed a coarse-grained bottom-up model,” Voth said, “where we captured information from atomic molecular dynamics simulations and from experiments.” He explained that the coarse-grained model solves only groups of atoms compared to simulations of all atoms, where each individual atomic interaction is resolved. “If you do well, which is always a challenge, you keep the physics in the model.”

Early study results show how protein proteins on the surface of the virus move together.

“They don’t move on their own like a bunch of random, uncoordinated movements,” Voth said. “They’re cooperating.”

This total protein protein movement is informative of how the coronavirus investigates and detects ACE2 receptors of a potential host cell.

“The article we published shows the beginnings of how the modes of movement in spike proteins are related,” Voth said. He added that the spikes are interconnected. When one protein moves, one responds as well.

“The ultimate goal of the model would be, as a first step, to examine the initial attractiveness of the virion and interactions with ACE2 receptors on cells and to understand the origin of this attraction and how these proteins participate in continuing the virus fusion process,” Voth said.

Simulation of coarse-grained molecular dynamics of SARS-CoV-2 virion using LAMMPS for time steps of 10 × 106 CG. Credit: Gregory Voth, University of Chicago.

Voth and his group have been developing coarse-grained methods to model viruses such as HIV and influenza for more than 20 years. They “deepen” the data to make it simpler and more computationally traceable, while remaining faithful to the dynamics of the system.

“The advantage of a coarse-grained model is that it can be a hundred to a thousand times more computationally efficient than a model with all atoms,” Voth explained. The computational savings allowed the team to build a much larger model of coronavirus than ever before, in longer time frames than was done with all-atom models.

“What you have left are much slower, collective motions. The effects of higher frequency, the motions of all atoms fold into these interactions if you do it well. It’s the idea of ​​systematic coarse grain.”

The integrated model developed by Voth began with atomic models of the four main structural elements of the SARS-CoV-2 virion: spike proteins, membranes, nucleocapsids, and envelopes. These atomic models were then simulated and simplified to create a complete model using a course.

Simulations of the molecular dynamics of all atoms of the spike protein component in the virion system, about 1.7 million atoms, were created by study co-author Rommie Amaro, a professor of chemistry and biochemistry at the University of California, San Diego.

“Their model basically consumes our data and can learn from these more detailed criteria based on the data we have, and then go beyond where we went,” Amaro said. “This method, developed by Voth, will allow us and others to simulate over the longer period of time needed to actually simulate a virus infecting a cell.”

Amaro described in more detail the behavior observed in coarse-grained protein simulations.

“What he saw very clearly was the beginning of the dissociation of the S1 tip subunit. The entire top of the tip peels off during fusion,” Amaro said.

One of the first steps of viral fusion with a host cell is this dissociation, where it binds to the ACE2 receptor of the host cell.

“The major S1 opening shifts seen with this coarse-grained model have not yet been seen in the molecular dynamics of all atoms and would actually be very difficult to see,” Amaro said. “It’s a critical part of the function of this protein and the host cell infection process. It was an interesting finding.”

The mode of motion of the SARS-CoV-2 virion along its own mode with the greatest variance, corresponding to the motion motion in the S1-S2 domain of the spike protein. Credit: Gregory Voth, University of Chicago.

Voth and his team used all-atom dynamic information about the open and closed state of the spike protein created by the Amaro lab on the Frontera supercomputer, as well as other data. The Frontera system, funded by the National Science Foundation (NSF), is operated by the Texas Advanced Computer Center (TACC) at the University of Texas at Austin.

“Frontera showed how important it is for these studies of the virus on multiple scales. At the atomic level, it was crucial to understand the basic dynamics of the tip with all its atoms. There is much to learn. But now this information can be used a second time to develop new methods , which allow us a longer and longer departure rate than the coarse grain method, ”Amaro said.

“Frontera has been particularly useful in providing data on molecular dynamics at the atomistic level for use in this model. It is very valuable,” Voth said.

The Voth group initially used the Midway2 computer cluster at the University of Chicago Research Computer Center to develop a coarse-grained model.

Simulations of all membrane and envelope protein atoms were created in the Anton 2 system. Anton 2, operated by the Pittsburgh Supercomputing Center (PSC) with support from the National Institutes of Health, is a special-purpose supercomputer for molecular dynamics simulations by DE Shaw Research developed and provided at no cost.

“Frontera and Anton 2 have provided key input at this model at the molecular level,” Voth said.

“The really fantastic thing about Frontera and these kinds of methods is that we can give people a much closer look at how these viruses move and do their job,” Amaro said.

“There are parts of the virus that are invisible even for experimentation,” she continued. “And with the kind of methods we use on Frontera, we can give scientists first and important insights into what these systems really look like in all their complexity and how they interact with antibodies or drugs or parts of a host cell.”

The range of information that Frontera provides to researchers helps to understand the basic mechanisms of viral infection. It is also useful for designing safer and better drugs to treat and prevent disease, Amaro added.

Said Voth: “One thing that worries us right now is the SARS-CoV-2 versions in the UK and South Africa. With a computer platform like the one we developed here, we can quickly assess these variations, which are changes. Amino acids. Hopefully, we can understand fairly quickly the changes these mutations cause to the virus, and then hope to help plan new modified vaccines going forward. ”

Scientists are creating the first computational model of the entire virus responsible for COVID-19

More information:
Alvin Yu et al, Multi-month coarse-grained viron model SARS-CoV-2, Biophysical Journal (2020). DOI: 10.1016 / j.bpj.2020.10.048

Provided by the University of Texas at Austin

Citation: The first complete coronavirus model shows the collaboration (2021, February 26) obtained on February 26, 2021 from

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