"Ion channels are like tiny molecular machines that sit on the surface of our cells in the lipid membrane. Like water faucets, they open and close allowing electrical current carried by charged particles to flow," says Jared Ostmeyer - a graduate student in the Benoit Roux Lab at the University of Chicago, IL, US.
With the help of some very specialized hardware, Ostmeyer is making big discoveries about the tiny, gated channels. "We're hoping to see the potassium channel open, close, or respond in some way to certain stimuli," he explains. Ostmeyer's research appears in the journal Nature.
"We didn't know why the top part of the channel would remain pinched shut for so long. It's an important biological question because many processes in the body depend on these channels remaining closed for an appropriate amount of time before opening again. Timing of the action potential - the electrical signal the channels help carry - is absolutely crucial, for example, in determining the rhythm of the heartbeat."
The cells Ostmeyer is investigating are easily identifiable across neurons, muscle tissue, and T-cells. Knowing the mechanisms behind what makes the channel gate open or close, and most importantly at what speed, have the potential to inform future research on neurological disorders like epilepsy, heart arrhythmias, and the development of improved pain killers and anesthetics.
Ostmeyer is now laying the foundation of understanding for what's happening with the slow inactivating gate of potassium channels and how it works. "The selectivity filter - the part of the channel that tells one ion type from another, (for example, potassium from sodium) - goes through a conformational change and can pinch shut, forming a gate at the top of the channel that blocks current from flowing through."
"What was really interesting was that this gate would remain closed for very long periods of time, sometimes longer than 10 seconds. We really had no idea why this conformation was so robustly stable."
To put this into perspective, the conformational transition is about one angstrom (one ten-billionth of a meter) of movement within the selectivity filter - about the width of a single atom. And it lasts for ten seconds or more, "a tremendous amount of time when you consider that's about how long it would take a bacteria to synthesize a completely brand new channel," says Ostmeyer.
"We discovered that water molecules become buried inside the channel in little cavities behind the selectivity filter. Once the water molecules are inside, the top part of the channel becomes pinched shut, blocking the flow of electrical current. Only after all of the water molecules leave, is the channel able to reopen, allowing electrical current to flow again. It's as if the conformational state of the channel is determined by whether or not water molecules are buried inside its protein structure."
"Knowing the important molecular events involved, we were able to use a technique - Umbrella Sampling - to repeatedly simulate each step along the molecular process. This helps when some steps occur infrequently. We ended up with a more complete picture by sampling every molecular step, rare or not, repeatedly many times."
Because the minute motions cannot be detected by any experimental technique, Ostmeyer and his colleagues use highly specialized supercomputing to simulate the channels and their surroundings. Such all-atom simulations are made possible thanks to the Anton supercomputer - donated by D.E. Shaw Research (DESRES) in collaboration with the National Resource for Biomedical Supercomputing - at Pittsburgh Supercomputing Center, in Pennsylvania, US.
"Anton is probably not best called a supercomputer; you can think of it as a lab device that does just one thing - millisecond-scale, molecular dynamics simulations," says David Shaw, founder and director of DESRES. Shaw spoke about Anton's custom-designed chips and algorithmic approach at the 22nd Annual ACM Symposium on High-Performance Parallel and Distributed Computing in New York City, US.
"In developing Anton, if we would have only developed a new architecture for standard algorithms, that would have turned out vastly slower. And if we had designed new algorithms for standard hardware it would still be much too slow," explains Shaw. "What we've done is tailor Anton for blindingly fast particle-particle interactions. The biophysical models that we use actually model the architectural opportunities and exploit them," says Shaw.
"We're getting extreme speedup by tailoring things to a physical model, that is, in turn tailored to our architecture. Communication is very carefully choreographed. Inside the chip data never moves in an arbitrary way or goes anywhere on the chip where it is not actively being used in a computation. Most computations from one time step to another happen right on the chip," notes, Shaw.
Anton's meticulously designed architecture enables Ostmeyer to observe molecular-level simulations of the channels for much longer periods of time. "No other supercomputer can run these types of simulations for as long as I can run them on Anton," says Ostmeyer. "We're able to run simulations that are tens of microseconds long. That's two orders of magnitude longer than I could run on any general supercomputing platform."
Along with the power of Anton, Ostmeyer attributes much of his success to meticulous preparation. He spent months building the virtual environment of the potassium channel, making sure every detail was accounted for and the simulation was set up correctly. "I had the appropriate number of ions, and protonation states of all the residues, and that actually paid off. If I hadn't taken the extra time to carefully set everything up, I would not have gotten the breakthrough results that I did."