Advertisement
Summary: Researchers present a molecular dynamics simulation of synaptic vesicle fusion from all atoms.
Source: Texas Advanced Computing Center
Let’s think for a second about thinking – specifically the physics of the 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 brains have billions of nerve cells, or neurons, and each neuron has thousands of connections to other neurons. The calibrated interactions of these neurons make up thoughts, whether the explicit kind — a distant memory surfacing — or the taken-for-granted kind — our peripheral awareness of our surroundings as we move through the world.
“The brain is an amazing communication network,” said Rizo-Rey. “When a cell is stimulated by electrical signals, synaptic vesicle fusion occurs very quickly. The neurotransmitters come out of the cell and bind to receptors on the synaptic side. That 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 intense study. So is the dysregulation of this process in neurons, which causes a variety of neurological diseases, from Alzheimer’s to Parkinson’s disease.
Decades of research has led to a thorough understanding of the key protein players and major steps involved in 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 that fuses with the plasma membrane at nerve endings and releases its contents into the opposite postsynaptic cell.
And longtime Rizo-Rey collaborator Thomas Südhof won the 2013 Nobel Prize in Medicine for his studies on the mechanisms that mediate neurotransmitter release (many with Rizo-Rey as a co-author).
But Rizo-Rey says his goal is to understand the specific physics of thought’s activation process in much more detail. “If I can understand that, winning the Nobel Prize would only be 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 explored this process and built and put a multi-million atom model of the proteins, the membranes and their environment virtually in motion to see what is happening, a process known as molecular dynamics.
registered mail eLife in June 2022, Rizo-Rey and co-workers presented molecular dynamics simulations of synaptic vesicle fusion for all atoms and provided insight into the primed state. The research reveals a system in which several specialized proteins are “spring-loaded,” just waiting for the supply of calcium ions to trigger fusion.
“It’s ready for release, but it’s not,” he explained. “Why not? It waits for the calcium signal. Neurotransmission is about the control of fusion. They want the system to be fusion-ready, so it can happen very quickly when calcium gets in, but it’s not fusioning yet.”
The study marks 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. In the last three decades he has 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 transmission in the brain. So I used other methods for a long time,” he said. “But with Frontera, I can model 6 million atoms and really get a picture of what’s going on with that 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 take place during this time. “When I see it starting, the lipids starting to mix, I’m asking for 5 million hours [the maximum time available] on Frontera,” he said, capturing the cracking of the spring-loaded proteins and the step-by-step process by which fusion and transfer occurs.
Rizo-Rey says the sheer amount of computation that can be used 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 at Frontera would have taken 10 years instead of a few months.”
Investing in basic research — and in the computer systems that support that type of research — is fundamental to the health and well-being of our nation, says Rizo-Rey.
“This country has been very successful because of basic research. Translation is important, but unless you have the basics of science, you have nothing to translate.”
See also
About this news from computational neuroscience research
Author: Aaron Dubrow
Source: Texas Advanced Computing Center
Contact: Aaron Dubrow—Texas Advanced Computing Center
Picture: Image is attributed to Jose Rizo-Rey, UT Southwestern Medical Center
Original research: Open access.
“Allatom molecular dynamics simulations of synaptotagmin-SNARE complexin complexes bridging a vesicle and a flat lipid bilayer” by Josep Rizo et al. eLife
abstract
Molecular dynamics simulations of all atoms of synaptotagmin-SNARE complexin complexes bridging a vesicle and a flat lipid bilayer
Synaptic vesicles are placed in a state ready for rapid neurotransmitter release at Ca2+– Binding to synaptotagmin-1. This condition likely 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 elucidate 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 fragments of synaptotagmin-1 and/or complexin-1.
Our results must be interpreted with caution due to the limited simulation times and lack of key components, but suggest mechanistic features that control release and may help visualize potential states of the primed synaptotagmin-1-SNARE complexin-1 complex.
The simulations suggest that SNAREs alone induce the formation of extensive membrane-membrane interfaces that can fuse slowly, and that the primed state contains macromolecular arrays of trans-SNARE complexes bound to synaptotagmin-1C2B domain and complexin-1 in a spring-loaded configuration that prevents premature membrane fusion and the formation of extended interfaces, but keeps the system poised for rapid fusion onto Ca2+ Influx.
