Using a supercomputer to understand synaptic transmission

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

Source: Texas Advanced Computing Center

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

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

Our brain has billions of nerve cells or neurons, and each neuron has thousands of connections with other neurons. The calibrated interactions of these neurons are what thoughts are made of, either of the explicit kind – a distant memory that emerges – or the kind taken for granted – our peripheral awareness of our surroundings as we move through the world.

“The brain is an amazing communications network,” said Rizo-Rey. “When a cell is excited by electrical signals, a very fast synaptic vesicle fusion occurs. Neurotransmitters leave the cell and bind to receptors on the synaptic side. This 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, which causes a number of neurological conditions, from Alzheimer’s disease to Parkinson’s disease.

Decades of research have led to an in-depth understanding of major protein players and broad tracts of membrane fusion for synaptic transmission. Bernard Katz received 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 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 mechanism that mediates the release of neurotransmitters (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 it, winning the Nobel Prize would be only a small reward,” she said.

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

Writing eVita in June 2022, Rizo-Rey and collaborators presented molecular dynamics simulations of all atoms of the synaptic vesicle fusion, providing a glimpse into the triggered state. The research shows a system in which several specialized proteins are “spring loaded”, just waiting for the delivery of calcium ions to trigger fusion.

“It’s ready for release, but it’s not,” he explained. “Why doesn’t he do it? He is waiting for the kick-off signal. Neurotransmission is about controlling fusion. You want the system to be ready for merging, so when the kick comes, it can happen very fast, but it’s not merging yet. “

Initial setup of molecular dynamics simulations designed to investigate the nature of the triggered 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. It has continued to use mainly experimental methods such as nuclear magnetic resonance spectroscopy for the past three decades to study the biophysics of the brain.

“The supercomputers weren’t powerful enough to solve the problem of how transmission took place in the brain. So for a long time I used other methods, ”she 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 microseconds of the fusion process, but his guess is that the act of fusion should take place at that time. “If I see how it’s starting, the lipids start mixing, I’m going to ask for 5 million hours [the maximum time available] about Frontera, “he said, to capture the snap of spring-loaded proteins and the step-by-step process by which fusion and transmission occurs.

Rizo-Rey says the sheer amount of computation that can be leveraged today is astounding. “We have a supercomputer system here at the University of Texas Southwestern Medical Center. I can use up to 16 knots, “he told her.” What I did on Frontera, instead of a few months, would have taken 10 years. “

Investing in basic research and the computer systems that support this type of research is critical to our nation’s health and well-being, says Rizo-Rey.

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

See also

About this computational neuroscience research news

Author: Aaron Dubrow
Source: Texas Advanced Computing Center
Contact: Aaron Dubrow – Texas Advanced Computing Center
Image: Image credit: Jose Rizo-Rey, UT Southwestern Medical Center

Original research: Free access.
“Molecular dynamics simulations of all atoms of Synaptotagmin-SNARE-complexin complexes connecting a vesicle and a flat lipid bilayer” by Josep Rizo et al. eVita


Simulations of the molecular dynamics of all atoms of the Synaptotagmin-SNARE-complexin complexes that connect a vesicle and a flat lipid bilayer

The synaptic vesicles are primed in a ready state for the rapid release of neurotransmitters onto Ca2+– by connecting to Synaptotagmin-1. This state likely includes trans-SNARE complexes between the vesicle and plasma membranes that are bound to synaptotagmin-1 and complexins.

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

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

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

Simulations suggest that SNAREs alone induce the formation of extensive membrane-to-membrane contact interfaces that can fuse slowly and that the triggered state contains macromolecular assemblies of Synaptotagmin-1 C-bound trans-SNARE complexes.2Domain B and complexin-1 in a spring-loaded configuration that prevents premature fusion of the membrane and the formation of extended interfaces, but keeps the system ready for rapid fusion on Ca2+ influx.