Using a supercomputer to understand synaptic transmission – Neuroscience News

Summary: The researchers present an all-atom molecular dynamic simulation of synaptic vesicle fusion.

Source: Texas Advanced Computing Center

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

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

Our brain contains 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, whether they be the explicit type – a distant memory that surfaces – or the taken-for-granted type – our peripheral awareness of our surroundings as we move through the world.

“The brain is an incredible communication network,” Rizo-Rey said. “When a cell is excited by electrical signals, a very rapid fusion of synaptic vesicles occurs. Neurotransmitters exit the cell and bind to receptors on the synaptic side. This is the signal and this process is very fast.

Exactly how these signals can occur so quickly – less than 60 microseconds or millionths of a second – is the subject of extensive study. The same goes for the dysregulation of this process in neurons, which causes a host of neurological disorders, from Alzheimer’s disease to Parkinson’s disease.

Decades of research have led to a thorough understanding of key protein players and outlines of membrane fusion for synaptic transmission. Bernard Katz was awarded the 1970 Nobel Prize in Medicine in part for demonstrating that chemical synaptic transmission consists of a synaptic vesicle filled with neurotransmitters fusing with the plasma membrane at nerve endings and releasing its contents into the opposite post-synaptic cell.

And longtime Rizo-Rey collaborator Thomas Südhof won the 2013 Nobel Prize in Medicine for his studies of the mechanisms that mediate neurotransmitter release (many with Rizo-Rey as a co-author).

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

Recently, using the Texas Advanced Computing Center’s (TACC) Frontera supercomputer, one of the most powerful systems in the world, Rizo-Rey explored this process, creating a multi-million atom model of proteins, membranes and their surroundings, and setting them in motion virtually to see what’s going on, a process known as molecular dynamics.

write in eLife in June 2022, Rizo-Rey and collaborators presented full-atom molecular dynamics simulations of synaptic vesicle fusion, providing insight into the primed 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.

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

Initial setup of molecular dynamics simulations designed to study 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 then used mostly experimental methods like resonance spectroscopy nuclear magnetic over the past three decades to study brain biophysics.

“Supercomputers weren’t powerful enough to solve this transmission problem 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 picture of what’s going on with this system.”

Rizo-Rey’s simulations only cover the first microseconds of the merging process, but his assumption is that the act of merging should occur at that time. “If I see how it starts, the lipids start to mix, then I’ll ask for 5 million hours [the maximum time available] on Frontera,” he said, to capture the snapping of spring proteins and the step-by-step process by which fusion and transmission occur.

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

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

“This country has had a lot of success with basic research. Translation is important, but if you don’t have the basic science, you have nothing to translate.

See also

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About this Computational Neuroscience Research News

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

Original research: Free access.
“All-atom molecular dynamics simulations of synaptotagmin-SNARE-complexin complexes linking a vesicle and a flat lipid bilayer” by Josep Rizo et al. eLife


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

Synaptic vesicles are primed into a state that is ready for the rapid release of neurotransmitters onto Ca2+-binding to Synaptotagmin-1. This state likely involves 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, 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 flat bilayers or a vesicle and a flat bilayer with or without synaptotagmin-1 and/or complexin-1 fragments. .

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

Simulations suggest that SNAREs alone induce the formation of extended membrane-membrane contact interfaces that can fuse slowly, and that the primed state contains macromolecular assemblies of trans-SNARE complexes linked to Synaptotagmin-1 C2Domain B and complexin-1 in a spring-loaded configuration that prevents premature fusion of membranes and the formation of extended interfaces, but keeps the system ready for rapid fusion on Ca2+ influx.

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