Using a supercomputer to understand synaptic transmission

Summary: The researchers present a molecular dynamic simulation of all the atoms in synaptic vesicle fusion.

Font: Texas Advanced Computing Center

Let’s think for a second about thought, specifically, the physics of neurons in the brain.

This topic has been the lifelong interest of José Rizo-Rey, Professor of Biophysics at the University of Texas Southwestern Medical Center.

Our brains have billions of nerve cells, or neurons, and each neuron has thousands of connections to other neurons. The calibrated interactions of these neurons are what thoughts are made of, whether it’s the explicit kind, a distant memory surfacing, or the kind that’s taken for granted, our peripheral awareness of our surroundings as we move through the world. .

“The brain is an amazing communications network,” Rizo-Rey said. “When a cell is excited by electrical signals, very rapid fusion of synaptic vesicles occurs. Neurotransmitters leave the cell and bind to receptors on the synaptic side. That is 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 study. So is the dysregulation of this process in neurons, leading to a host of neurological conditions, from Alzheimer’s to Parkinson’s disease.

Decades of research have led to a deep understanding of the major protein players and the broad features of membrane fusion for synaptic transmission. Bernard Katz received the 1970 Nobel Prize in Medicine in part for showing that chemical synaptic transmission consists of a neurotransmitter-filled synaptic vesicle fusing with the plasma membrane at nerve endings and releasing its contents into the opposite postsynaptic cell.

And Rizo-Rey’s longtime collaborator Thomas Südhof won the Nobel Prize in Medicine in 2013 for his studies on the machinery that mediates neurotransmitter release (many with Rizo-Rey as a co-author).

But Rizo-Rey says his goal is to understand the specific physics of how the thought activation process occurs in much more detail. “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 has been exploring this process, creating a multimillion-dollar atom model of proteins, membranes, and their environment and virtually set them in motion to see what happens, a process known as molecular dynamics.

writing in eLife in June 2022, Rizo-Rey and colleagues presented molecular dynamics simulations of all atoms from synaptic vesicle fusion, giving a glimpse of the primed state. The research shows a system in which several specialized proteins are “spring-loaded”, waiting only for the supply of calcium ions to trigger fusion.

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

This shows a computer generated image of a synaptic vesicle.
Initial setup of molecular dynamics simulations designed to investigate the nature of the primed state of synaptic vesicles. Credit: Jose Rizo-Rey, UT Southwestern Medical Center

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. He went on to use primarily experimental methods such as magnetic resonance spectroscopy. nuclear power for the past three decades to study the biophysics of the brain.

“Supercomputers weren’t powerful enough to solve this problem of how transmission occurs in the brain. So for a long time I used other methods,” he said. “However, with Frontera, I can model 6 million atoms and really get a sense 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 act of fusion should occur at that time. “If I see how it starts, the lipids start to mix, then I will ask for 5 million hours [the maximum time available] at Frontera,” he said, to capture the snapping of spring-loaded proteins and the step-by-step process by which fusion and transmission occur.

Rizo-Rey says that the sheer amount of computing that can be harnessed today is incredible. “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 in Frontera, instead of a few months, would have taken 10 years.”

Investing in basic research, and in the information systems that support this type of research, is critical to the health and well-being of our nation, 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.”

See also

This shows the asymmetric structures of the brain.

About this computational neuroscience research news

Author: Aaron Dubrow
Font: Texas Advanced Computing Center
Contact: Aaron Dubrow – Texas Advanced Computing Center
Image: Image is credited to Jose Rizo-Rey, UT Southwestern Medical Center

original research: Open access.
Molecular dynamics simulations of all atoms of Synaptotagmin-SNARE-complexin complexes linking a vesicle and a planar lipid bilayer” by Josep Rizo et al. eLife


Molecular dynamics simulations of all atoms of Synaptotagmin-SNARE-complexin complexes linking a vesicle and a planar lipid bilayer

Synaptic vesicles are primed in a state that is ready for the rapid release of neurotransmitters on Ca2+-binding to Synaptotagmin-1. This state likely includes trans-SNARE complexes between the vesicle and plasma membranes that bind Synaptotagmin-1 and complexins.

However, the nature of this state and the steps leading to membrane fusion remain unclear, in part due to the difficulty of experimentally studying this dynamic process.

To shed light on these questions, we performed all-atom molecular dynamics simulations of systems containing trans-SNARE complexes between two planar bilayers or a vesicle and a planar bilayer with or without Synaptotagmin-1 and/or complexin-1 fragments.

Our results should be interpreted with caution due to limited simulation times and the absence of key components, but suggest mechanistic features that may control release and help visualize potential states of the primed Synaptotagmin-1-SNARE-complexin-1 complex.

Simulations suggest that SNAREs alone induce the formation of extended membrane-membrane contact interfaces that can slowly fuse, and that the primed state contains macromolecular assemblies of trans-SNARE complexes bound to Synaptotagmin-1 CtwoDomain B and complexin-1 in a spring-loaded configuration that prevents premature fusion of membranes and formation of extended interfaces, but keeps the system ready for rapid fusion with Ca2+ influx.

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