Excitatory neurotransmitters are molecules that are used by nerves to bridge the synaptic cleft between nerve cells and stimulate other nerves into firing. While key to the operation of our nerves, excitatory neurotransmitters can also contribute to brain damage in the wake of injuries or strokes. Now, researchers using supercomputing at the Pittsburgh Supercomputing Center (PSC) have uncovered a potential new pathway for halting that damaging overactivity.
Specifically, the researchers looked at glutamate (an amino acid that serves as the main excitatory neurotransmitter in vertebrate species) and the NMDA family of receptor proteins that respond to glutamate transmissions. Importantly, glutamate must be accompanied by either D-serine or glycine (two other amino acids) when it docks with NMDA receptors. “When one neuron wants to communicate with another, it releases glutamate into the synaptic cleft,” explained Albert Lau, a professor of biophysics and biophysical chemistry at the Johns Hopkins School of Medicine, in an interview with PSC’s Ken Chiacchia. “Some glycine or D-serine is there, too.”
The team set out to understand the differences in how NMDA receptors responded to glutamate and D-serine using molecular dynamics simulations on PSC’s Anton-2 supercomputer. The 128-node Anton-2 system (which remains off the Top500) is purpose-built for molecular dynamics simulations. This strength was critical for the research, as the researchers needed to simulate as much binding time as they could to best understand the behavior of the molecules.
The supercomputer-powered simulations enabled a startling discovery: D-serine could also bind to other subunits of the receptor, which meant that – in large enough quantities – D-serine could actually block reception of glutamate, rather than enabling it. The in silico discovery was corroborated by live cell experiments at the Cold Spring Harbor Laboratory. While many tests remain (e.g. to see if brains can sustain high enough D-serine levels), the new information opens the path to possible use of glutamate to ameliorate brain damage from injuries or strokes.
“Anton was crucial [for this work]. Initially, when we approached this project, we wanted to look at differences in binding pathways to the NMDA receptor between glutamate and D-serine,” Lau said. “Anton was the perfect resource to use for this computational experiment because it required long-timescale simulations … to look at these different binding pathways.”
To learn more about this research, read the reporting from PSC’s Ken Chiacchia here. You can also read the paper, which was published in eLife as “Excitatory and inhibitory D-serine binding to the NMDA receptor,” here.