The COVID-19 virus is a mystery. Scientists stay in the dark about aspects of how it fuses and gets into the host cell; how it is composed; and how it buds from the host cell.

Computer modeling combined with experimental data provides insights into these behaviors. The modeling of the pandemic-causing SARS-CoV-2 virus using meaningful time scales has so far been limited to its parts such as the spike protein, a target for the current vaccination round.

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

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

“We developed a coarse-grained bottom-up model,” said Voth, “using information from molecular dynamics simulations at the atomic level and from experiments.” He explained that a coarse-grained model only resolves groups of atoms, as opposed to all-atom simulations, in which every single atomic interaction is resolved. “If you do this well, which is always a challenge, keep the physics in the model.”

The early results of the study show how the spike proteins move cooperatively on the surface of the virus.

“They don’t move independently like random, uncorrelated movements,” said Voth. “They work together.”

This cooperative movement of the spike proteins is informative of how the coronavirus explores and detects the ACE2 receptors of a potential host cell.

“The paper we published shows the beginnings of the correlation of the modes of movement in the spike proteins,” said Voth. He added that the spikes are paired together. When one protein moves, another 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 understand the origins of that attraction and understand how these proteins work together to move on to the virus fusion process,” said Voth.

Voth and his group have been developing coarse-grained modeling methods for viruses such as HIV and influenza for more than 20 years. They “coarsen” the data in order to make them easier and more computationally comprehensible, while they remain true to the dynamics of the system.

“The advantage of the coarse-grained model is that it can be hundreds to a thousand times more computationally efficient than the all-atom model,” explained Voth. The computational savings allowed the team to create a much larger model of the coronavirus than ever before, and over longer periods of time than all-atom models.

“What you are left with are the much slower, collective movements. The effects of the higher frequency allatomic movements will fold into these interactions if you do it well. That is the idea of ​​systematic coarse graining.”

The holistic model developed by Voth began with atomic models of the four main structural elements of the SARS-CoV-2 virion: spike, membrane, nucleocapsid and envelope proteins. These atomic models were then simulated and simplified to create the complete granular model.

The molecular dynamic all-atom simulations of the spike protein component of the Virion system, approximately 1.7 million atoms, were created by study co-author Rommie Amaro, professor of chemistry and biochemistry at the University of California at San Diego.

“Your model basically takes our data, and it can learn from the data we have at these more granular scales and then go beyond where we’ve gone,” said Amaro. “This method, developed by Voth, enables us and others to simulate, over extended periods of time, the time required to actually simulate the virus that infects a cell.”

Amaro discussed the behavior observed from the coarse-grain simulations of the spike proteins.

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

One of the first steps in virus fusion with the host cell is this dissociation, during which it binds to the host cell’s ACE2 receptor.

“The larger S1 opening motions they saw with this coarse-grained model we hadn’t seen in the molecular dynamics of all atoms, and in fact it would be very difficult for us to see them,” said Amaro. “It’s a critical part of this protein’s function and the process of infecting the host cell. That was an interesting finding.”

Voth and his team used the allatomic information about the open and closed states of the spike protein generated 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 Computing Center (TACC) at the University of Texas at Austin.

“Frontera has shown how important it is for this multi-level study of the virus. At the atomic level, it was crucial to understand the underlying dynamics of the tip and all of its atoms. There is still a lot to learn there. But now there is still a lot to learn. ” This information can be used a second time to develop new methods that allow us to go longer and further, such as the coarse grain method, “Amaro said.

“Frontera was particularly useful in providing the molecular dynamics data at the atomic level to feed into this model. It is very valuable,” said Voth.

The Voth Group first used the Midway2 computer cluster at the Research Computing Center at the University of Chicago to develop the coarse-grained model.

The membrane and envelope protein allatom simulations were generated on the Anton 2 system. Anton 2 is operated by the Pittsburgh Supercomputing Center (PSC) with the support of the National Institutes of Health and is a special supercomputer for molecular dynamics simulations that is developed and provided free of charge by DE Shaw Research.

“Frontera and Anton 2 provided the most important input data at the molecular level for this model,” said Voth.

“One of the really fantastic things about Frontera and these methods is that we can give people much more accurate views of how these viruses move and do their jobs,” said Amaro.

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

The type of information Frontera gives researchers helps understand the basic mechanisms underlying viral infection. It’s also useful in developing safer and better drugs to treat and prevent the disease, Amaro added.

Voth said: “One thing that worries us at the moment is the British and South African SARS-CoV-2 variants. Presumably, with a computing platform like the one we have developed here, we can quickly evaluate these deviations, which are changing Hopefully we can understand pretty quickly the changes these mutations are causing in the virus, and then hopefully help develop new modified vaccines. “

The study “A coarse-grained multiscale model of the SARS-CoV-2 virion” was published on November 27, 2020 in the Biophysical Journal. The study is coauthored by Alvin Yu, Alexander J. Pak, Peng He, Viviana Monje-Galvan, and Gregory A. Voth of the University of Chicago; and Lorenzo Casalino, Zied Gaieb, Abigail C. Dommer, and Rommie E. Amaro from the University of California at San Diego. Funded by the NSF through NSF RAPID grant CHE-2029092, NSF RAPID MCB-2032054, the National Institute of General Medical Sciences of the National Institutes of Health through grant R01 GM063796, National Institutes of Health GM132826, and a UC San Diego Moore’s SARS-COV-2 Seed Grant for Cancer Center 2020. Computing resources were funded by the Research Computing Center at the University of Chicago, Frontera from the Texas Advanced Computer Center, funded through the NSF Grant (OAC-1818253), and the Pittsburgh Super Computing Center (PSC) provided via the Anton 2 machine. Computer time for Anton 2 was allocated by the COVID-19 HPC Consortium and provided by the PSC through Grant R01GM116961 from the National Institutes of Health. The Anton 2 machine at PSC was generously made available by DE Shaw Research. “

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