Coronavirus protein vibrations may play a role in infection

When someone is having trouble opening a lock with a key that doesn’t quite seem to work, sometimes it can help to shake the key a bit. Now, new research from MIT suggests that coronaviruses, including the one that causes COVID-19, may use a similar method to trick cells into leaving viruses inside. The results could be useful in determining how dangerous different strains or mutations of coronavirus can be and could indicate a new approach to the development of treatments.

Studies of how spike proteins, which give coronaviruses their distinct crown-shaped appearance, interact with human cells typically involve biochemical mechanisms, but for this study, the researchers took a different approach. Using atomistic simulations, they examined the mechanical aspects of how spike proteins move, shape, and vibrate. The results indicate that these vibrational movements could explain a strategy used by coronaviruses, which can trick a locking mechanism on the cell surface by leaving the virus through the cell wall so that it can hijack the reproductive mechanisms of the cell. cell.

The team found a strong direct relationship between the rate and intensity of spike vibrations and the ease with which the virus could enter the cell. They also found an opposite relationship with the death rate of a given coronavirus. Because this method is based on understanding the detailed molecular structure of these proteins, the researchers say it could be used to screen for emerging coronaviruses or new COVID-19 mutations, to quickly assess their potential risk.

The findings, by MIT civil and environmental engineering professor Markus Buehler and graduate student Yiwen Hu, are published today in the print edition of the journal Material after going live on October 30.

All the pictures we see of the SARS-CoV-2 virus are a bit misleading, according to Buehler.

“The virus doesn’t look like that,” he says, because in reality all nanoscale matter of atoms, molecules and viruses “is continually moving and vibrating. They don’t really look like these pictures in one. chemistry. book or website. “

Buehler’s laboratory specializes in atom-by-atom simulation of biological molecules and their behavior. As soon as COVID-19 emerged and information about the protein composition of the virus became available, Buehler and Hu, a doctoral student in mechanical engineering, took action to see if the mechanical properties of proteins played a role. role in their interaction with humans. body.

The tiny nanoscale vibrations and shape changes of these protein molecules are extremely difficult to observe experimentally, so atomistic simulations are useful in understanding what is going on. The researchers applied this technique to examine a crucial stage of infection, when a viral particle with its protein peaks attaches to a human cell receptor called the ACE2 receptor. Once these spikes bind to the receptor, it unlocks a channel that allows the virus to enter the cell.

This binding mechanism between proteins and receptors works something like a lock and a key, and that’s why vibrations are important, according to Buehler. “If it’s static, it’s just okay or bad,” he said. But protein peaks are not static; “They continuously vibrate and change shape slightly, and that’s important. The keys are static, they don’t change shape, but what if you had a key that continually changes shape – it vibrates, it moves, it changes slightly? They will adapt differently depending on how they look the moment we put the key in the lock. “

The more the “key” can change, the researchers reason, the more likely it is to find an adjustment.

Buehler and Hu modeled the vibrational characteristics of these protein molecules and their interactions, using analytical tools such as “normal mode analysis”. This method makes it possible to study the way in which vibrations develop and propagate, by modeling atoms as point masses connected to each other by springs which represent the different forces acting between them.

They found that differences in vibrational characteristics were strongly correlated with different rates of infectivity and case fatality of different types of coronavirus, drawn from a global database of confirmed case numbers and case fatality rates. The viruses studied included SARS-CoV, MERS-CoV, SATS-CoV-2, and a known mutation of the SARS-CoV-2 virus which is increasingly prevalent around the world. This makes this method a promising tool for predicting the potential risks of emerging new coronaviruses, as they likely will, Buehler says.

In all of the cases they’ve studied, says Hu, a crucial part of the process is the upward fluctuation of one branch of the protein molecule, making it accessible to bind to the receptor. “This movement is of significant functional importance,” she says. Another key indicator has to do with the relationship between two different vibrational motions in the molecule. “We find that these two factors show a direct relationship with the epidemiological data, the infectivity of the virus and also the lethality of the virus,” she said.

The correlations they found mean that when new viruses or new mutations in existing viruses appear, “you can filter them out from a purely mechanical point of view,” Hu said. “You can just look at the fluctuations in these spike proteins and find out how they can act epidemiologically, such as the degree of infection and the severity of the disease.”

Potentially, these findings could also provide a new avenue for research into possible treatments for COVID-19 and other coronavirus illnesses, Buehler says, speculating that it would be possible to find a molecule that would bind to advanced proteins of ‘a way that would stiffen them and limit their vibrations. Another approach could be to induce opposing vibrations to cancel the natural vibrations in the tips, in the same way that noise canceling headphones suppress unwanted sound.

As biologists learn more about the different types of mutations that occur in coronaviruses and identify areas of genomes most likely to change, this methodology could also be used predictively, Buehler says. The types of mutations most likely to emerge could all be simulated, and those with the most dangerous potential could be flagged so that the world could be alerted to watch for any signs of the actual emergence of these particular strains. Buehler adds: “The G614 mutation, for example, which currently dominates the spread of COVID-19 around the world, is expected to be slightly more infectious, according to our findings, and slightly less fatal.”

Mihri Ozkan, professor of electrical and computer engineering at the University of California at Riverside, who was not connected to this research, says this analysis “highlights the direct correlation between nanomechanical characteristics and lethality and infection rate. of coronavirus. I believe his work is advancing the field significantly in finding information on the mechanisms of disease and infection. “

Ozkan adds that “if under natural environmental conditions the overall flexibility and mobility ratios predicted in this work occur, identifying an effective inhibitor that can lock spike protein to prevent binding could be a holy grail. prevention of SARS-CoV-2 infections, which we all desperately need. ”

This story is republished courtesy of MIT News (web.mit.edu/newsoffice/), a popular site that covers current affairs in MIT’s research, innovation and education.