When someone struggles to open a lock with a key that doesn't quite seem to
work, sometimes jiggling the key a bit will help. Now, new research from MIT
suggests that coronaviruses, including the one that causes Covid-19, may use
a similar method to trick cells into letting the viruses inside. The
findings could be useful for determining how dangerous different strains or
mutations of coronaviruses may be, and might point to a new approach for
developing treatments.
Studies of how spike proteins, which 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 motions could account for a strategy that
coronaviruses use, which can trick a locking mechanism on the cell's surface
into letting the virus through the cell wall so it can hijack the cell's
reproductive mechanisms.
The team found a strong direct relationship between the rate and intensity
of the spikes' vibrations and how readily the virus could penetrate the
cell. They also found an opposite relationship with the fatality 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 emerging coronaviruses or new mutations of Covid-19, to
quickly assess their potential risk.
The findings, by MIT professor of civil and environmental engineering Markus
Buehler and graduate student Yiwen Hu, are being published today in the
print edition of the journal Matter after being posted online on October 30.
All the images 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 matter
down at the nanometer scale of atoms, molecules, and viruses "is
continuously moving and vibrating. They don't really look like those images
in a chemistry book or a website."
Buehler's lab specializes in atom-by-atom simulation of biological molecules
and their behavior. As soon as Covid-19 appeared and information about the
virus' protein composition became available, Buehler and Hu, a doctoral
student in mechanical engineering, swung into action to see if the
mechanical properties of the proteins played a role in their interaction
with the human 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 taking place. The researchers applied
this technique to look at a crucial step in infection, when a virus particle
with its protein spikes attaches to a human cell receptor called the ACE2
receptor. Once these spikes bind with the receptor, that unlocks a channel
that allows the virus to penetrate the cell.
That binding mechanism between the proteins and the receptors works
something like a lock and key, and that's why the vibrations matter,
according to Buehler. "If it's static, it just either fits or it doesn't
fit," he says. But the protein spikes are not static; "they're vibrating and
continuously changing their shape slightly, and that's important. Keys are
static, they don't change shape, but what if you had a key that's
continuously changing its shape -- it's vibrating, it's moving, it's
morphing slightly? They're going to fit differently depending on how they
look at the moment when we put the key in the lock."
The more the "key" can change, the researchers reason, the likelier it is to
find a fit.
Buehler and Hu modeled the vibrational characteristics of these protein
molecules and their interactions, using analytical tools such as "normal
mode analysis." This method is used to study the way vibrations develop and
propagate, by modeling the atoms as point masses connected to each other by
springs that represent the various forces acting between them.
They found that differences in vibrational characteristics correlate
strongly with the different rates of infectivity and lethality of different
kinds of coronaviruses, taken from a global database of confirmed case
numbers and case fatality rates. The viruses studied included SARS-CoV,
MERS-CoV, SATS-CoV-2, and of one known mutation of the SARS-CoV-2 virus that
is becoming increasingly prevalent around the world. This makes this method
a promising tool for predicting the potential risks from new coronaviruses
that emerge, as they likely will, Buehler says.
In all the cases they have studied, Hu says, a crucial part of the process
is fluctuations in an upward swing of one branch of the protein molecule,
which helps make it accessible to bind to the receptor. "That movement is of
significant functional importance," she says. Another key indicator has to
do with the ratio between two different vibrational motions in the molecule.
"We find that these two factors show a direct relationship to the
epidemiological data, the virus infectivity and also the virus lethality,"
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 of these spike proteins and
find out how they may act on the epidemiological side, like how infectious
and how serious would the disease be."
Potentially, these findings could also provide a new avenue for research on
possible treatments for Covid-19 and other coronavirus diseases, Buehler
says, speculating that it might be possible to find a molecule that would
bind to the spike proteins in a way that would stiffen them and limit their
vibrations. Another approach might be to induce opposite vibrations to
cancel out the natural ones in the spikes, similarly to the way
noise-canceling headphones suppress unwanted sounds.
As biologists learn more about the various kinds of mutations taking place
in coronaviruses, and identify which areas of the genomes are most subject
to change, this methodology could also be used predictively, Buehler says.
The most likely kinds of mutations to emerge could all be simulated, and
those that have the most dangerous potential could be flagged so that the
world could be alerted to watch for any signs of the actual emergence of
those particular strains. Buehler adds, "The G614 mutation, for instance,
that is currently dominating the Covid-19 spread around the world, is
predicted to be slightly more infectious, according to our findings, and
slightly less lethal."
Reference:
Hu Y, Buehler MJ. Comparative Analysis of Nanomechanical Features of
Coronavirus Spike Proteins and Correlation with Lethality and Infection
Rate. Matter. 2020. doi:
10.1016/j.matt.2020.10.032
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