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Using a supercomputer to understand synaptic transmission

Overview: Researchers present an all-atom molecular dynamic simulation of synaptic vesicle fusion.

Source: Texas Advanced Computing 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 neurons, and 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 is excited by electrical signals, very rapid synaptic vesicle fusion takes place. The neurotransmitters come out of the cell and bind to receptors on the synaptic side. That is the signal and this process is going 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 lines 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.

Sign up eLife in June 2022, Rizo-Rey and co-workers presented all-atom molecular dynamics simulations of synaptic vesicle fusion, giving them a glimpse of the primed state. The research demonstrates a system in which several specialized proteins are “spring-loaded”, waiting for only the delivery of calcium ions to cause fusion.

“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 to have the system ready to fuse, so if 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 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

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 weren’t 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 it start, 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 takes place.

Rizo-Rey says the sheer amount of computing power that can be harnessed today is unbelievable. “We have a supercomputing 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 10 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 thanks to fundamental research. Translation is important, but if you don’t have the basic science, you have nothing to translate.”

Also see

This shows the asymmetric structures of the brain

About this computational neuroscience research news

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

Original research: Open access.
All-atom Molecular Dynamics Simulations of Synaptotagmin-SNARE Complexin Complexes Bridging a Vesicle and a Flat Lipid Bilayerby Josep Rizo et al. eLife


All-atom Molecular Dynamics Simulations of Synaptotagmin-SNARE Complexin Complexes Bridging a Vesicle and a Flat Lipid Bilayer

Synaptic vesicles are primed for rapid release of neurotransmitters on Ca2+binding to Synaptotagmin-1. This condition probably involves trans-SNARE complexes between the vesicle and plasma membranes 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 planar bilayers or a vesicle and a planar bilayer with or without fragments of Synaptotagmin-1 and/or complexin. -1.

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

The simulations suggest that only SNAREs 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 bound to the Synaptotagmin-1 C2B domain and complexin-1 in a spring-loaded configuration that prevents premature membrane fusion and formation of extended interfaces, but keeps the system ready for rapid fusion at Ca2+ influx.

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