In recent months, scientists have learned a lot about the mechanisms of this meaningless enemy, but what we have learned is still pale in the face of what we don’t know.
There are a number of tactics in which scientists notice how a virus works, and only through these tandem strategies can we locate and exploit the weak problems of coronavirus, explains Ahmet Yildiz, associate professor of physics and molecular mobile biology at the University of California, Berkeley. .
Yildiz and his collaborator Mert Gur of Istanbul Technical University mix simulations of molecular dynamics of pc with experiments in a single molecule to uncover the secrets of the virus. In component, its complex protein (S), the component of the virus that joins human cells. and initiates the procedure of placing viral RNA in the cell.
“Many teams are addressing other stages of this process,” Gur said. “Our initial purpose is to use molecular dynamics simulations to identify the processes that occur when the virus joins the host cell. “
There are 3 critical stages that allow the complex protein to enter the mobile and begin to replicate, explains Yildiz.
First, the complex protein will have to move from a closed to an open configuration; Second, the complex protein joins your outdoor receiver from our mobile phones; This binding triggers a replacement in the conformation within the complex protein and allows other humans protein to split the tip. Finally, the newly exposed surface of the image interacts with the host’s moving membrane and allows viral RNA to enter and divert the mobile.
In early February, electron microscope photographs revealed the complex protein design, but snapshots showed only the main configurations taken through the protein, not the transition steps between the steps. “We only see snapshots of solid conformations,” Yildiz said. Because we don’t know the timing of the occasions that allow the protein to move from one solid conformation to the next, we don’t know those intermediate conformations yet. “
This is where computer modeling comes in. Microscopic photographs provide a useful starting point for creating models of protein atoms and their environment (water, ions, and mobile receptors). From there, Yildiz and Gur put the protein in motion and observed what had happened.
“We have shown that protein S passes in an intermediate state before it can be anchored to the receptor protein in the host’s moving membrane,” Gur said. “This intermediate condition would possibly be helpful in directing medications to prevent protein S from starting a viral infection. “
While many other computers around the world are investigating the virus binding bag, hoping to find a drug that can prevent the virus from sticking to human cells, Yildiz and Gur take a more nuanced approach.
“Complex protein strongly joins your receptor with a complex interaction network,” Yildiz explained. “We’ve shown that if you just interrupt one of those interactions, you still can’t avoid the link. That’s why some of the key studies on drug progression may not produce the desired results. “
But if it is imaginable to prevent the peak protein from going from a closed state to an open state, or a third intermediate state that we are not even aware of in the open state, it may simply lend the to treatment.
Find and break links
At the time PC simulations are used through Yildiz and Gur, not only are new states known, but also express state stabilizing amino acids.
“If we can discover the vital bonds at the point of an unmarried amino acid, whose interactions stabilize and are essential for those confirmations, it would possibly be imaginable to target those states with small molecules,” Yildiz said.
Simulating this habit at the point of the individual atom or amino acid is incredibly computational. Yildiz and Gur were given time at the Stampede2 supercomputer at the Texas Advanced Computing Center (TACC), the fastest supercomputer of the moment at an American university and the 19th overall, thanks to the COVID-19 HPC Consortium. Simulating a micromoment of the virus and its interactions with human cells – about one million atoms in total – takes weeks in a supercomputerArray . . . and it would take years without one.
“It’s not an easy procedure in terms of calculation,” Yildiz said, “but the predictive force of this is very blunt. “
The Yildiz and Gur team, along with approximately 40 other study teams that read COVID-19, have gained precedence over TACC systems. “We are not limited by the speed at which simulations occur, so there is a real-time race between our ability to run simulations and analyze data. “
Over time, Gur and his collaborators made calculations, reconstructing the atomic pilgrimages of the complex protein as it approaches, joins and interacts with angiotensin conversion enzyme 2 (ACE2) receptors, proteins that line the surface of many mobile types.
Their first results, which proposed lifestyles of an intermediate semi-open state of protein S compatible with molecular dynamics (MD) simulations of the RBD-ACE2 bond of all atoms, were published in the Journal of Chemical Physics.
In addition, through active MD simulations of all atoms, they learned an extensive network of saline bridges, hydrophobic and electrostatic interactions, and hydrogen bonds between the complex protein receptor binding domain and ACE2. The effects of these findings have been found in BioRxiv.
The mutation of residues in the receptor binding domain was not enough to destabilize the bond, but reduced the average paints to unleash the complex ace2 protein. They recommend that blocking this site through a neutralizing antibody or nanobody can be an effective strategy for inhibiting complex protein. ACE2 interactions.
To verify that data received through PC is accurate, Yildiz’s team conducted laboratory experiments on the movement of fluorescence resonance power to a single molecule (or smFRET), a biophysical strategy used to measure distances on a scale of 1 to 10 nanometers in unique molecules.
“The strategy is to see the protein’s conformal settings by measuring the energy movement between two light-emitting probes,” Yildiz said.
Although scientists do not yet have a strategy to see the main atomic points of moving molecules in real time, the combination of electron microscopy, images of single molecules and computer simulations can provide researchers with an image of the virus’s behavior, Yildiz said.