Studies suggest that the mechanical properties of peak proteins may predict infectivity and mortality of various coronaviruses.
When someone struggles to open a lock with a key that does not quite seem to work, it can sometimes help to tilt the key a little. Now, new research from WITH suggests that coronavirus, including that which causes Covid-19, may use a similar method to trick cells into letting the viruses inside. The results could be useful in determining how dangerous different strains or mutations of coronavirus can be, and may point to a new approach to the development of treatments.
Studies of how spike proteins that give coronaviruses their distinct crown-like appearance interact with human cells typically involve biochemical mechanisms, but for this study, the researchers took a different approach. Using atomistic simulations, they looked at the mechanical aspects of how the spike proteins move, change shape and vibrate. The results indicate that these vibrational movements may explain a strategy used by the coronavirus, which may trick a locking mechanism on the cell surface to allow the virus through the cell wall so that it can hijack the cell’s reproductive mechanisms.
The team found a strong direct relationship between the speed and intensity of the vibrations of the spikes and how easily the virus could enter the cell. They also found an opposite relationship to the mortality of a given coronavirus. Because this method is based on an understanding of the detailed molecular structure of these proteins, the researchers say it could be used to screen for new coronaviruses or new mutations in Covid-19 to quickly assess their potential risk.
The results of MIT professor of civil and environmental engineering Markus Buehler and graduate student Yiwen Hu are published in the journal Fabric.
All the pictures we see of SARS-CoV-2 virus is a bit misleading, according to Buehler. “The virus does not look like that,” he says, because in reality everything means the nanometer scale for atoms, molecules and viruses “moves constantly and vibrates. They do not really look like these pictures in a chemistry book or a website. ”
Buehler’s laboratory specializes in atomatom atom simulation of biological molecules and their behavior. As soon as Covid-19 appeared 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 the proteins played a role in their interaction with the human body.
The small nanoscale vibrations and deformations of these protein molecules are extremely difficult to observe experimentally, so atomistic simulations are useful for understanding what is going on. The researchers used this technique to look at a crucial step in the infection when a virus particle with its protein tips binds to a human cell receptor called the ACE2 receptor. When these spikes bind to the receptor, it unlocks a channel that allows the virus to enter the cell.
This binding mechanism between the proteins and receptors acts somewhat like a lock and key, which is why the vibrations matter, according to Buehler. “If it’s static, it just fits, or it does not fit,” he says. But the protein tips are not static; “They vibrate and continuously change their shape a little, and that is important. Keys are static, they do not change shape, but what if you had a key that is constantly changing its shape – it vibrates, it moves, it changes a little? They will fit differently depending on how they look the moment we put the key in the lock. ”
The more the “key” can change, the researchers justify, the more likely it is to find a fit.
Buehler and Hu modeled the vibration properties of these protein molecules and their interactions using analytical tools such as “normal mode analysis”. This method is used to study the way in which vibrations develop and multiply, by modeling the atoms as point masses connected to each other by springs representing the different forces acting between them.
They found that differences in vibration characteristics strongly correlate with the different rates of infectivity and mortality of different types of coronavirus, taken from a global database of confirmed case numbers and deaths in cases. The viruses studied included SARS-CoV, MERS-CoV, SATS-CoV-2 and a known mutation of SARS-CoV-2 virus that is becoming more and more widespread worldwide. This makes this method a promising tool for predicting the potential risks of new coronaviruses occurring as they are likely to, Buehler says.
In all the cases they have studied, Hu says, a crucial part of the process is fluctuations in an upward oscillation of a branch of the protein molecule, which helps make it available 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 movements in the molecule. “We find that these two factors show a direct relationship to the epidemiological data, the virus infectivity and also the virus mortality,” she says.
The correlations they found mean that when new viruses or new mutations of existing ones appear, “you could screen them from a purely mechanical side,” Hu says. “You can just look at the fluctuations in these spike proteins and find out how they can work on the epidemiological side, like how contagious and how serious the disease would be.”
Potentially, these findings could also provide a new path to research into possible treatments for Covid-19 and other coronavirus diseases, Buehler says, speculating that it may be possible to find a molecule that would bind to the tip proteins in a way that would stiffen them and limit their vibrations. Another approach may be to induce opposite vibrations to remove the natural ones in the spikes in the same way that noise-canceling headphones suppress unwanted sounds.
As biologists learn more about the different types of mutations that take place in the coronavirus and identify which areas of the genomes are most prone to change, this method can also be used predictably, Buehler says. The most likely types of mutations that should occur could all be simulated, and those with the most dangerous potential could be marked so that the world could be warned to look for signs of the actual emergence of the particular strains. Buehler adds: “The G614 mutation, which dominates the Covid-19 spread worldwide, for example, is predicted by our findings to be slightly more contagious and slightly less lethal.”
Mihri Ozkan, professor of electrical and computer engineering at the University of California at Riverside who was not associated with this research, says this analysis “points to the direct link between nanomechanical features and coronavirus mortality and infection rate. I believe that his work leads the field markedly rather than finding insight into the mechanics of diseases and infections. ”
Ozkan adds that “If under the natural environmental conditions there is an overall flexibility and mobility conditions predicted in this work, identification of an effective inhibitor that can lock the tip protein to prevent binding can be a holy grail to prevent SARS-CoV- 2 infections that we all desperately need now. ”
Reference: “Comparative analysis of nanomechanical features of Coronavirus spike proteins and correlation with mortality and infection rate” by Yiwen Hu and Markus J. Buehler, October 30, 2020, Fabric.
DOI: 10.1016 / j.matt.2020.10.032
The research was supported by the MIT-IBM Watson AI Lab, the Office of Naval Research and the National Institutes of Health.