3D structures are often insufficient to truly understand the function of proteins


Posted February 22, 2021 by beauty33

The first 3D protein structure began in 1970s, and nowadays Protein Data Bank has hundreds of thousands of protein information.
 
The first 3D protein structure began in 1970s, and nowadays Protein Data Bank (a world-class three-dimensional structure information bank for large biomolecules) has hundreds of thousands of protein information.

Computer simulation technology is developing rapidly, and in the next few decades, computers will be able to establish and increase the behavioral understanding of proteins by setting up 3D molecular machines and analyzing the energy landscape, interactions, and dynamics of proteins, allowing us to understand the driving force of life more.

Recently, DeepMind threw an explosive news that its precise artificial intelligence prediction shocked the entire protein structure world.

In November 2020, Science published some views on the field by Ken Dill, director of the Laufer Center for Physics and Quantitative Biology at Stony Brook University in New York, and academician of the National Academy of Sciences, and colleagues Carlos Simmerling and Emiliano Brini.

The article says: "Computational molecular physics is an increasingly powerful tool to describe the role of protein molecules, and enhanced sampling methods and accelerator system improvements enable (computational molecular physics) to reach the scale of important biological effects. At such a rate, in the next 25 years, it is within tens of minutes to describe what protein molecules do throughout the life cycle of bacterial cells. "

However, several decades after the first protein dynamics model was introduced, computational biophysicists still faced significant challenges. First of all, the results need to be available, then the simulation needs to be accurate; in order to be accurate, it needs an atom and an atom to advance femtosecond by femtosecond; in order to match the key time scale, the simulation must be extended to subtle or millisecond, that is, millions of time steps.

"At the rate of development of computational molecular physics, it is not enough to allow us to enter the time, size, and range of motion we need to see," the authors said. One of the main ways structural biology researchers understand proteins is called molecular dynamics. For example, the Dill team has been working on developing a molecular dynamics simulation called MELD to accelerate this process by providing vague but important information to MELD.

Next Dill describes what researchers can do using MELD.

One of the most important uses of biophysical models in our daily life is the discovery and development of drugs, and viral or bacterial 3D models are most helpful in identifying weak links in their defense systems. First, molecular dynamics simulations can determine which small molecules may bind to attackers and disrupt them, but these predictive results of them also need to work with other teams to experimentally test their accuracy.

The Dill group also used Frontera, a supercomputer at the Texas Advanced Computing Center, to scan millions of commercially available small molecules and then collaborated with Dima Kozakov's group at Stony Brook University to determine their effectiveness against COVID-19.

The third project is to study an interesting cellular protein called PROTAC, which guides human cells’ "garbage collection proteins" to collect specific target proteins that are not usually removed.

"Our cells have smart ways to identify proteins that need to be destroyed. Close to them and label them, then take them away by the protein that collects the trash. Initially, PROTAC molecules were used to target cancer-associated proteins. Now, there is a push to move this concept to targets against the SARS-CoV-2 protein. "

In collaboration with Peter Tonge, a chemist at Stony Brook University, they are working to model the interaction of novel PROTAC with the COVID-19 virus. “These are our most ambitious simulations, and Frontera is an important resource that can give us enough turnaround time, both from the scale of the system we are dealing with and from the chemical complexity. For one simulation, we need 30 GPUs and 4 to 5 days of continuous computation.” says Dill.

The team is developing and testing their protocols on non-COVID test systems, and they will apply this design process to the COVID system when it is accurate.

Each protein has a story to tell, and Dill, Brini, and their collaborators are establishing and applying tools to help elucidate these stories. Dill concluded: "There are some problems in protein science, and we believe that the real challenge is to properly use physics and mathematics and then verify hypotheses."
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Issued By https://www.creative-biostructure.com/
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Last Updated February 22, 2021