Using a supercomputer to understand synaptic transmission

How the brain prepares to think

Initial configuration of the molecular dynamics simulations designed to investigate the nature of the primed state of synaptic vesicles. Credit: Jose Rizo-Rey, UT Southwestern Medical Center

Let’s think for a moment about thinking, especially about the physics of neurons in the brain.

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

Our brains have billions of nerve cells or neuronsand each neuron has thousands of connections to other neurons. The calibrated interactions of these neurons is what thoughts are made of, whether it be the explicit kind — a distant memory that surfaced — or the self-evident kind — our peripheral awareness of our environment as we move through the world.

“The brain is an amazing communication network,” says Rizo-Rey. “When a cell gets excited by electrical signals, very fast synaptic vesicle fusion takes place. The neurotransmitters come out of the cell and bind to receptors on the synaptic side. That’s the signal and this process is very fast.”

How exactly these signals can occur so quickly — less than 60 microseconds or millionths of a second — is the focus of intense research. The same goes for the dysregulation of this process in neurons, which causes a wide range of neurological disorders, from Alzheimer’s disease to Parkinson’s disease.

Decades of research have led to a thorough understanding of the key protein players and the broad outlines of membrane fusion for synaptic transmission. Bernard Katz was awarded the Nobel Prize in Medicine in 1970, in part for demonstrating that chemical synaptic transmission consists of a neurotransmitter-filled synaptic vesicle that fuses with the plasma membrane at nerve endings and releases its contents to the opposing postsynaptic cell. And Rizo-Rey’s longtime collaborator, Thomas Südhof, won the Nobel Prize in Medicine in 2013 for his research on the machinery that mediates neurotransmitter release (many co-authored by Rizo-Rey).

But Rizo-Rey says his goal is to understand in much more detail the specific physics of how the thought activation process takes place. “If I can understand that, winning the Nobel Prize would be just a small reward,” he said.

Recently, using the Frontera supercomputer at the Texas Advanced Computing Center (TACC), one of the most powerful systems in the world, Rizo-Rey investigated this process and created a multi-million atomic model of the proteins, the membranes and their environment. and set them in motion virtually to see what happens, a process known as molecular dynamics.

How the brain prepares to think

Configuration of the primed synaptotagmin-SNARE-complexin complex suggested by molecular dynamics simulations. Credit: Jose Rizo-Rey, UT Southwestern Medical Center

Sign up eLife in June 2022, Rizo-Rey and collaborators presented all-atom molecular dynamics simulations of synaptic vesicle fusion, providing glimpses of the primed state. The study demonstrates a system in which several specialized proteins are “spring-loaded”, awaiting only the delivery of calcium ions bring about a merger.

“It’s ready to be released, but it doesn’t,” he explained. “Why not? It’s waiting for the calcium signal. Neurotransmission is about controlling fusion. You want the system ready to fuse, so when calcium comes in, it can happen very quickly, but it’s not fusing yet.”

The study represents a return to computational approaches for Rizo-Rey, who recalls using the original Cray supercomputer at the University of Texas at Austin in the early 1990s. Subsequently, for the past three decades, he mainly used experimental methods such as nuclear magnetic resonance spectroscopy to study the biophysics of the brain.

“Supercomputers were not powerful enough to solve this problem of how transmission took place in the brain† So I’ve been using other methods for a long time,” he said. “However, with Frontera I can model 6 million atoms and really get a picture of what’s going on with this system.”

Rizo-Rey’s simulations only cover the first few microseconds of the fusion process, but his hypothesis is that the fusion should take place during that time. “When I see how it starts, the lipids start mixing, then I ask for 5 million hours [the maximum time available] on Frontera,” he said, to capture the snap of the spring-loaded proteins and the step-by-step process by which the fusion and transfer occurs.

Rizo-Rey says the sheer amount of computing power that can be harnessed today is unbelievable. “We have a supercomputer system here at the University of Texas Southwestern Medical Center. I can use up to 16 nodes,” he said. “What I did on Frontera would have taken ten years instead of a few months.”

Investing in basic research — and in the computer systems that support this kind of research — is fundamental to our country’s health and well-being, says Rizo-Rey.

“This country was very successful because of basic research. Translation is important, but if you don’t have the basic science, you have nothing to translate.”

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More information:
Josep Rizo et al, All-atom molecular dynamics simulations of Synaptotagmin-SNARE complexin complexes bridging a vesicle and a flat lipid bilayer, eLife (2022). DOI: 10.7554/eLife.76356

Journal information:

Quote: Using a supercomputer to understand synaptic transmission (2022, June 20) retrieved June 25, 2022 from

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