The secret of cell energy revealed by a supercomputer


Supercomputer simulations have shown for the first time how mitochondrial voltage-dependent anion channels (VDACs) of cells bind to the enzyme hexokinase-II (HKII). Artist’s impression 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 body’s own membrane protein VDAC (dark blue). ATP (red) is phosphorylated by HKII. This basic research helps researchers understand the molecular basis of diseases like cancer. Credits: Haloi, N., Wen, PC. , Cheng, Q. et al.

As the saying goes, tango costs two.

This is especially true for scientists who study how cells work in detail. 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.

The migration of a compound called adenosine triphosphate (ATP) from the mitochondria, which drives the cells, is important for the energy supply of the cells. The interaction of a protein enzyme called hexokinase II (HKII) with a voltage-dependent anion channel (VDAC) protein in the outer mitochondrial membrane is important for this outflow into the energy-consuming parts of the cell. is.

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

This basic research on the interaction of proteins from the driving force of the cell, the 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.”

Tajkhorschid, Nature communication biology The study found that when enzymes and channel proteins bind together, channel conduction changes and the flow of ATP is partially blocked. Simulations on the Stampede2 system from TACC have shown this coupling.

In addition, the ranch system, which is associated with TACC’s XSEDE, maintains an external permanent 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 and several of these simulations are required. I need a copy of this. It’s scientifically compelling. It doesn’t work without XSEDE. We have to study smaller systems again, ”says Tajkhorshid.

This study not only concerns 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 and provides a “handle” for the cell to use. Hexokinase-II causes conversion, binds in mitochondrial channels, swallows ATP and phosphorylates.

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

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

Tajkhorshid’s team has developed the most detailed and sophisticated model of the complex made up of the bond between HKII and VDAC, which combines all atoms with the highest resolution. Molecular dynamics simulation Use the coarser method of Brownian dynamics. The system size of the VDAC-HKII complex was about 700,000 atoms including the membrane. That’s about a fifth the diameter of the COVID-19 virus.

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

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

Wen explained that their simulation design began with the hypothesis that the VDAC protein in the outer membrane could fully interact with HKII, which is located in different parts of the cell called the cytosol. They speculated that HKII should first bind to the membrane 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, the researchers split 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 the molecular dynamics of all atoms and tools developed by a center called the Highly Mobile Membrane Model (HMMM), which studies membrane interactions. I used it.

Next, we used Brownian dynamics to study how HKII drifts on the membrane to conform to the VDAC and many encounter / collision events between the seated VDAC and the drift HKII on the planar membrane. created.

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

“At the beginning of this process, the long time scale from milliseconds to seconds in all-atom simulations seemed almost impossible,” said Nandan, co-author of the study and doctoral student at the center, “said Halloy.

Many other computational science tools have been developed by the group, including NAMD, which is widely 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 with NAMD code. Otherwise you need them. We couldn’t reach the time frame, ”says Tajkhorshid.

“I am very satisfied with the support from TACC and TACC for most of the projects and software development, software tuning and acceleration, and this work. TACC is great to support us, ”said Tajkhorshid. Lord says.

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

The next step in the study will involve more ambitious systems like merging the two. cellIt is important to understand how neurons in the brain signal each other. And how new viruses like the coronavirus fuse with host cells.

Tajkhorshid’s group has been assigned leadership resources for the NSF-funded flagship supercomputer Frontera at TACC to investigate some of these ambitious projects.

“Our research deals with molecular systems and processes, how molecules bind, how they work and how people change their structure in order to achieve a certain function,” says Tajkhorshid. I like to see it as a computer microscope that can see. “Measure indirectly and experimentally. Supercomputers are essential to providing 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 informations:
Nandan Haloi et al., Structural basis for the 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 Received September 21

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