Using a supercomputer to understand synaptic transmission

Summary: Researchers show a whole atomic molecular dynamic simulation of the synthesis of a synaptic vesicle.

A source: Texas Advanced Computing Center

Let’s think about thinking, or more precisely, the physics of neurons in the brain.

This topic has been of lifelong interest to Jose Rizo-Rey, a professor of biophysics at the University of Texas Southwest Medical Center.

There are billions of nerve cells or neurons in our brains, and each neuron has thousands of connections with other neurons. This is the calibrated interaction of neurons, the explicit form of thought — the surfing or perception of distant memory — our peripheral consciousness as we travel the world.

“The brain is a wonderful network of communication,” Rizo-Ray said. “When a cell is stimulated by electrical signals, the synthesis of synaptic vesicles occurs very quickly. Neurotransmitters leave the cell and bind to receptors on the synaptic side. It’s a signal and the process is very fast. “

How these signals come to be so quickly in less than 60 microseconds, or a fraction of a millionth of a second, is the focus of intense research. The same is true of this process in neurons, which cause many neurological conditions, from Alzheimer’s to Parkinson’s disease.

Decades of research have led to a thorough understanding of the major protein players and the broader shocks of membrane synthesis for synaptic transmission. Bernard Katz was awarded the Nobel Prize in Medicine in 1970 for showing that a partial chemical synaptic transmission combines with the plasma membrane at the opposite nerve endings of a synaptic vesicle filled with neurotransmitters to release its contents into the postsynaptic cell.

Rizo-Rey’s longtime collaborator, Thomas Südhof, won the 2013 Nobel Prize in Medicine for his research into neurotransmitter-secreting mechanisms (mostly as a Rizo-Ray co-author).

However, Rizo-Ray says that his goal is to gain a deeper understanding of specific physics in terms of how the process of activation of thought occurs. “If I could understand, winning the Nobel Prize would be a small prize,” he said.

Using the Frontera supercomputer (TACC), one of the most powerful systems in Texas, Rizo-Ray recently studied this process and created a multi-million atomic model of proteins, membranes, and cells. This process, which drives them into virtual motion to see their environment and what is happening, is called molecular dynamics.

to write eLife In June 2022, Rizo-Ray and colleagues demonstrated a simulation of the entire atomic molecular dynamics of the synthesis of a synaptic vesicle, which looked at the initial state. The study shows a “spring-loaded” system of several specialized proteins that wait only for the delivery of calcium ions to bind.

“It’s ready to release, but it’s not,” he explained. “Why not? It is waiting for the calcium signal. On the management of neurotransmission synthesis. You want to be ready to dissolve the system, so when calcium comes in, it can dissolve very quickly, but it hasn’t dissolved yet. ”

The initial configuration of molecular dynamic simulations is designed to study the nature of the initial state of synaptic vesicles. Credit: Jose Rizo-Rey, UT Southwest Medical Center

The study marks a return to computational methods for Rizo-Ray, which recalls the use of the original Cray supercomputer at the University of Texas at Austin in the early 1990s. In the last three decades, he began to use experimental methods such as nuclear magnetic resonance spectroscopy to study the biophysics of the brain.

“Supercomputers have not been strong enough to solve the problem of what is being transmitted in the brain. So for a long time I used other methods, ”he said. “But with Frontera, I can model 6 million atoms and really see what’s going on in this system.”

Rizo-Rey’s simulations cover only the first few microseconds of the merger process, but his hypothesis is that the merger act must have taken place at that time. “If I see how it starts and the lipids start to mix, I ask for 5 million hours. [the maximum time available] At the front, ”he said, to capture the process of merging and transferring spring proteins regularly and in stages.

According to Rizo-Rey, the sheer volume of calculations used today is staggering. “We have a supercomputer system at the University of Texas Southwest Medical Center. I can use 16 nodes, ”he said. “What I do at the front will take 10 years instead of a few months.”

Investing in basic research and computing systems that support this type of research is the foundation of our country’s health and well-being, says Rizo-Ray.

“This country has been very successful thanks to fundamental research. Translation is important, but if you don’t have a fundamental knowledge, you have nothing to translate. ”

See also

This shows the asymmetrical structures of the brain

This is about a computational neurology research report

Author: Aaron Dabrow
A source: Texas Advanced Computing Center
The connection: Aaron Dabrow – Texas Advanced Computing Center
Photo: Photo courtesy of Jose Rizo-Rey, UT Southwest Medical Center

Original study: Open access.
Joseph Reza eLife


The simulation of the total atomic molecular dynamics of the Synaptotagmin-SNARE-complex combines a vesicle and a flat lipid double layer.

Synaptic vesicles are made ready for the rapid release of neurotransmitters to Ca2+– Binding to Synaptotagmin-1. This condition most likely involves Synaptotagmin-1 and trans-SNARE complexes between vesicle and plasma membranes associated with complexes.

However, the nature of this situation and the steps leading to membrane fusion are unclear due to the difficulty of studying this dynamic process experimentally.

To shed light on these questions, we performed a simulation of the entire atomic molecular dynamics of systems containing two flat double layers or trans-SNARE complexes between vesicles and flat double layers with or without fragments of synaptotagmin-1 and / or complex-1.

Due to limited simulation time and the lack of key components, our results should be interpreted with caution, but we offer mechanical functions that will control the release and help visualize the potential state of the prepared Synaptotagmin-1-SNARE-complexin-1 complex.

Simulations show that only SNAREs have extended membrane-to-membrane contact interfaces that can be slowly reached, and that the primer contains a macromolecular complex of trans-SNARE complexes associated with Sinaptotagmin-1C.twoIn the domain and complex-1 spring-loaded configuration, it prevents premature coupling of the membrane and the formation of extended interfaces, but keeps the system ready for rapid coupling with Ca.2+ influx.

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