The secret of cellular energy revealed by a supercomputer


Supercomputer simulations have revealed for the first time how voltage-dependent anion channels in mitochondrial cells (VDACs) bind to the enzyme hexokinase-II (HKII). An artistic representation 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, the tango costs two.

This is especially true for scientists who study 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 the activities of others.

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

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

This basic research into how proteins interact with the cell’s driving force, 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, “It was a million dollar question.

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

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

“Without XSEDE, we couldn’t afford to study many of these complex biological projects and systems because we couldn’t afford to execute them. Usually long simulations are required and several of these simulations. I need a copy. It is scientifically convincing. It is impossible without XSEDE. We have to go back to studying smaller systems, ”says Tajkhorshid.

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

Basically, cells need ATP to metabolize glucose. The “P” is used to convert glucose into 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 validated experimentally,” explains 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, that’s good. For cancer cells, it also helps cells grow and proliferate, ”he said.

The Tajkhorshid 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 size of the VDAC-HKII complex system was approximately 700,000 atoms including the membrane. It is about a fifth of the diameter of the COVID-19 virus.

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

The Stampede2 (left) and Ranch (right) systems receive resources from the Extreme Science and Engineering Discovery Environment (XSEDE) funded by the National Science Foundation (NSF). 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 localized in different parts of the cell called the cytosol. They hypothesized that HKII should first bind to the membrane and drift onto the membrane until it reaches the VDAC protein.

The VDAC on the membrane is already well modeled, and based on this knowledge, the 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 the molecular dynamics of all atoms and tools developed by a center called the Highly Mobile Membrane Model (HMMM) which deals with membrane interactions. I used it.

Next, using Brownian dynamics, we investigated how HKII drifts on the membrane to adapt to VDAC, and numerous encounter / collision events between the seated VDAC and the drift HKII on the plane membrane. created.

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

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

Many other computer tools have been developed by the group, in particular 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 will need it. We couldn’t reach the timescale, ”explains Tajkhorshid.

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

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

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

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

“Our research focuses on molecular systems and processes, how molecules bind together, how they work, and how people change their structure to achieve a particular function,” Tajkhorshid said. I like to think of it as a computer microscope that can see. ”Measure indirectly and experimentally. Supercomputers are essential in providing this level of detail and can be used to understand the molecular basis of disease, drug discovery, etc. “

Researchers elucidate the mechanism of protein transport in mitochondria

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

Provided by
Texas Advanced Computing Center

Quote: Secrets of Cellular Energy Revealed on Supercomputers (September 21, 2021) from https: // 2021 Obtained September 21

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