The secret of cellular energy revealed by a supercomputer

Supercomputer simulations have revealed for the first time how cell mitochondrial voltage-dependent anion channels (VDACs) bind to the enzyme hexokinase-II (HKII). An artistic depiction of the formation of a complex of the cytosolic enzyme hexokinase (light blue) on the surface of the outer membrane of mitochondria followed by the endogenous membrane protein VDAC (dark blue). ATP (red) is phosphorylated by HKII. This basic research helps researchers understand the molecular basis of diseases such as cancer. Credits: Haloi, N., Wen, PC. , Cheng, Q. et al.

As the saying goes, tango costs two.

This is especially true for scientists who are studying the details of how cells work. Intracellular protein molecules interact with other proteins, and in a sense proteins dance with their partners to respond to signals and regulate each other’s activities.

Important for giving cells the energy of life is the migration of a compound called adenosine triphosphate (ATP) from the mitochondria that drive the cells. And what is important for this outflow to the power-consuming parts of the cell is the interaction of a protein enzyme called hexokinase-II (HKII) with a voltage-dependent anion channel (VDAC) protein in the outer mitochondrial membrane. is.

Supercomputer simulations have revealed for the first time how VDACs bind to HKII. This task was supported by an assignment awarded by the Extreme Science and Engineering Discovery Environment (XSEDE) on the Stampede2 system at the Texas Advanced Computing Center (TACC). XSEDE is funded by the National Science Foundation.

This basic research on how proteins interact from the cell’s driving force, mitochondria, helps researchers understand the molecular basis of diseases such as cancer.

Emad Tajkhorshid, Chairman of the Biochemistry Donation Committee, J. Woodland Hastings, University of Illinois at Urbana-Champaign, said: “That was a million dollar question.”

Tajkhorshid, Nature Communications Biology The study found that when enzymes and channel proteins bind to each other, channel conduction changes and ATP flow is partially blocked. Simulations on TACC’s Stampede2 system revealed this coupling.

In addition, the Ranch system assigned to TACC’s XSEDE maintains offsite persistent file storage for research data.

“Without XSEDE, we couldn’t afford to study many of these complex projects and biological systems because we couldn’t afford to run them. Usually, long simulations are needed and multiple of these simulations. I need a copy of it. It’s scientifically compelling. It’s impossible without XSEDE. We have to go back to studying smaller systems, “says Tajkhorshid.

This study affects not only healthy cells, but also a deeper understanding of cancer cells.

Basically, cells need ATP to metabolize glucose. The “P” is used to convert glucose to glucose phosphate, providing a “handle” that the cell can use. Hexokinase-II causes conversion, binds in mitochondrial channels, swallows ATP, and phosphorylates.

“We have shown how phosphorylation affects the binding process between two proteins, which has also been experimentally validated,” says Tajkhorshid.

VDAC channels are important for the direct and efficient delivery of ATP to hexokinase. “It can act like a double-edged sword. For healthy cells it’s good. For cancer cells, it also helps the cells promote and proliferate,” he said.

Tajkhorshid’s team has developed the most detailed and sophisticated model of the complex formed by the binding of HKII and VDAC to date, combining all atoms with the highest resolution. Molecular dynamics simulation Use the coarser Brownian dynamics method. The system size of the VDAC-HKII complex was about 700,000 atoms including the membrane. This is about one-fifth the diameter of the COVID-19 virus.

Po-Chao Wen, a postdoctoral fellow at the NIH Polymer Modeling and Bioinformatics Center at the University of Illinois at Urbana-Champaign, said:

The secret of cellular energy revealed by a supercomputer

The Stampede2 (left) and Ranch (right) systems are allocated resources from the National Science Foundation (NSF) -funded Extreme Science and Engineering Discovery Environment (XSEDE). Credit: TACC

Wen explained that their simulation design began with the hypothesis that the VDAC protein in the outer membrane could interact entirely with HKII, which is localized in different parts of the cell called the cytosol. They speculated that HKII should bind to the membrane first and drift on the membrane until it reaches the VDAC protein.

The VDAC on the membrane is already well modeled, and based on this knowledge, researchers decomposed the modeling of the HKII-VDAC complex into three parts, initially focusing on HKII.

To study how HKII binds to the outer membrane of mitochondria, they use all-atom molecular dynamics and tools developed by a center called the Highly Mobile Membrane Model (HMMM) that deals with membrane interactions. I used it.

Next, using Brownian dynamics, we studied how HKII drifts on the membrane to fit the VDAC, and many encounter / collision events between the sitting VDAC and the drift HKII on the planar membrane. created.

“Next, we used whole-atom molecular dynamics to obtain a more sophisticated model of the interaction and a particular size, and looked for this particular protein-protein interaction,” Wen added. .. This helped find the most stable complex of the two proteins formed.

“The long millisecond to second timescale of all-atom simulations seemed almost impossible when we started this process,” said Nandan, a co-author of the study and a PhD student at the center.・ Halloy said.

Many other computational science tools have been developed by the group, including NAMD, which is commonly used in molecular dynamics.

“These are very expensive calculations and cost millions of dollars to set up independently, and you have to run them on a parallel supercomputer using NAMD code. Otherwise, you’ll need them. We couldn’t reach the timescale, “says Tajkhorshid.

“I am very pleased with TACC and TACC’s support for most projects and software development, software tuning and acceleration, as well as this work. TACC is great for supporting us,” said Tajkhorshid. Mr. says.

TACC scientists are working with the NIH Polymer Modeling and Bioinformatics Center to constantly optimize the NAMD software currently used by thousands of researchers.

The next step in the study will include more ambitious systems such as the fusion of the two. cell, It is important to understand how neurons in the brain signal each other. And how new viruses, such as coronavirus, fuse with host cells.

Tajkhorshid’s group was awarded leadership resource allocation for NSF-funded flagship supercomputer Frontera at TACC to investigate some of these ambitious projects.

“Our research is about molecular systems and processes, how molecules bind, how they work, and how people change structure to achieve a particular function,” said Tajkhorshid. I like to see it as a computational microscope that can see. ” Measure indirectly and experimentally. Supercomputers are essential to provide this level of detail and can be used to understand the molecular basis of disease, drug discovery, and more. ”

Researchers elucidate the mechanism of protein transport in mitochondria

For more information:
Nandan Haloi et al, Structural basis for complex formation between mitochondrial anion channel VDAC1 and hexokinase-II, Communication biology (2021). DOI: 10.1038 / s42003-021-02205-y

Quote: Cell energy secrets revealed on supercomputers (September 21, 2021) from https: // 2021 Obtained on September 21st

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The secret of cellular energy revealed by a supercomputer

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