UChicago Researchers Leverage Anton Simulations to Explore Protein Dynamics

June 10, 2024

June 10, 2024 — Malfunction of the proteins that sense voltage changes in our nerve cells underlies a number of human diseases throughout the body. A University of Chicago team used an Anton 2 supercomputer developed by D. E. Shaw Research and hosted at PSC to simulate a voltage-sensing protein from a primitive animal to learn how the sensor part of the protein behaves.

This image shows the complexity of simulating the functional movements of the voltage-sensitive phosphatase’s motions. Anton 2 enables scientists to reproduce the movements of the protein’s components, as well as the lipids (grey, with the headgroups colored), water molecules (blue dots), and ions (yellow/orange spheres) that are essential for a faithful reproduction of the protein in the computer. Credit: Spencer Guo.

Their simulations uncovered an unexpected series of motions that hadn’t been predicted by earlier work. The findings gave scientists a new perspective on the complexity of these proteins that may someday help direct design of drugs for human conditions caused by their dysfunctions.

Every movement, thought, and impression we have is a complicated dance of electrical charges running through our brains. Our nerve cells produce electrical signals by first building an imbalance of electrically charged ions (mainly sodium and potassium) across their cell membranes. When a nerve cell receives a signal to fire, it does so by allowing that imbalance to collapse. Tiny channel proteins open up, allowing the ions to flow. As the channels open up, the change in voltage caused by the ion flow causes channels farther down the cell’s long axon to fire up as well. This starts a chain reaction of voltage change down the axon, toward the nerve or muscle cell that receives the signal next. This is called an action potential.

Problems with these voltage-gated ion channels underlie a number of human diseases. In the brain, they can cause epilepsy, ataxia (problems with walking), migraine, deafness, and night blindness. In the electrically sensitive heart muscles, they can cause irregular heartbeats. They can also cause kidney disease and many other conditions.

Doctors would like to understand better how voltage-sensitive channels work. That’s not exactly easy, as they contain two complex parts: the domain that senses voltage changes, and the channel domain itself. But a series of proteins in a number of species have a voltage-sensing domain attached to a simple enzyme protein rather than a complicated channel. These voltage-sensitive phosphatases offer a way of focusing only on the voltage-sensing part.

Spencer Guo, a graduate student working with Aaron Dinner and Benoit Roux at the University of Chicago, wanted to get a better idea of how the voltage-sensitive domain of the phosphatase works in the sea squirt Ciona intestinalis. This species is a primitive worm-like chordate that is more closely related to us than to actual worms. The experimental structure of this protein was previously determined by Eduardo Perozo’s laboratory. Rong Shen, a staff scientist also involved in the present study, initiated computational studies of it. By simulating how this protein reacts to changes in voltage across a cell membrane, Guo and his teammates could glean clues as to how the more complex voltage-sensitive channels work in humans.

To carry out this challenging series of simulations, the team turned to Anton, a special-purpose supercomputer for molecular dynamics simulation that was designed and constructed by D. E. Shaw Research (DESRES); a second-generation Anton machine is made available without cost by DESRES, and is hosted at PSC with operational funding support by the National Institutes of Health.

While the phosphatase Guo was studying would be simpler to simulate in the computer than the channel proteins, the task still wouldn’t be easy. The voltage sensor consists of what for all the world looks like a screw sitting in a socket that itself sits in the cell membrane. X-ray pictures of the motionless protein suggested that the screw might, in response to voltage changes, partly “unscrew” itself, with that motion relayed to the enzyme part of the protein to activate it.

Crucial to visualizing the motion of this protein in action was the Anton supercomputer at PSC, which has the ability to carry out simulations of biomolecules orders of magnitude more quickly than general-purpose supercomputers.

“Most people, when they run simulations, and [particularly on] Anton 2, tend to run very long single or a few simulations … But for our methods, it can be actually more advantageous to run relatively short simulations, and then we statistically combine them,” explained Guo. “In our case, we still had, I think, something like 400 total microseconds. We ran [about] one microsecond simulation at a time on Anton 2, and that took about 45 minutes to an hour. If you were to do it on a GPU cluster, or the cluster that we have [at the university], that would take about three days at least.”

Guo would need to use Anton a little differently than most scientists. Instead of running very long simulations, which is a unique strength of Anton, he’d need to carry out many short simulations, because the motions of the sensor could be very quick, but could also vary with each repetition because of random movements. By carrying out many short simulations, Guo could sample many examples of the different key motions contributing to activation and characterize their importance statistically — in other words, they could see what the average motion was and how much it differed when repeated.

The simulations were eye opening. Rather than the “screw” part of the protein moving partly up and out of the socket in coordination with its rotation and the changes in interactions of the protein side chains, the three sets of movements were only loosely coupled. The outward movement, rotation, and changes in side-chain interactions could happen in varying order. Importantly, the work captured a number of states for the protein that hadn’t been directly detected by laboratory methods.

The team reported these results in the journal Nature Communications in February 2024. In particular, their paper suggests ways of validating their findings on real voltage-sensing phosphatase in the laboratory that could in turn spur better simulations. Such a game of ping-pong between lab and computer holds promise in sharpening scientists’ understanding of how these proteins work and how their behavior can be affected by drugs intended to reverse human diseases.


Source: Ken Chiacchia, PSC

Subscribe to HPCwire's Weekly Update!

Be the most informed person in the room! Stay ahead of the tech trends with industry updates delivered to you every week!

HPE and NVIDIA Join Forces and Plan Conquest of Enterprise AI Frontier

June 20, 2024

The HPE Discover 2024 conference is currently in full swing, and the keynote address from Hewlett-Packard Enterprise (HPE) CEO Antonio Neri on Tuesday, June 18, was an unforgettable event. Other than being the first busi Read more…

Slide Shows Samsung May be Developing a RISC-V CPU for In-memory AI Chip

June 19, 2024

Samsung may have unintentionally revealed its intent to develop a RISC-V CPU, which a presentation slide showed may be used in an AI chip. The company plans to release an AI accelerator with heavy in-memory processing, b Read more…

ASC24 Student Cluster Competition: Who Won and Why?

June 18, 2024

As is our tradition, we’re going to take a detailed look back at the recently concluded the ASC24 Student Cluster Competition (Asia Supercomputer Community) to see not only who won the various awards, but to figure out Read more…

Qubits 2024: D-Wave’s Steady March to Quantum Success

June 18, 2024

In his opening keynote at D-Wave’s annual Qubits 2024 user meeting, being held in Boston, yesterday and today, CEO Alan Baratz again made the compelling pitch that D-Wave’s brand of analog quantum computing (quantum Read more…

Apple Using Google Cloud Infrastructure to Train and Serve AI

June 18, 2024

Apple has built a new AI infrastructure to deliver AI features introduced in its devices and is utilizing resources available in Google's cloud infrastructure.  Apple's new AI backend includes: A homegrown foun Read more…

Argonne’s Rick Stevens on Energy, AI, and a New Kind of Science

June 17, 2024

The world is currently experiencing two of the largest societal upheavals since the beginning of the Industrial Revolution. One is the rapid improvement and implementation of artificial intelligence (AI) tools, while the Read more…

HPE and NVIDIA Join Forces and Plan Conquest of Enterprise AI Frontier

June 20, 2024

The HPE Discover 2024 conference is currently in full swing, and the keynote address from Hewlett-Packard Enterprise (HPE) CEO Antonio Neri on Tuesday, June 18, Read more…

Slide Shows Samsung May be Developing a RISC-V CPU for In-memory AI Chip

June 19, 2024

Samsung may have unintentionally revealed its intent to develop a RISC-V CPU, which a presentation slide showed may be used in an AI chip. The company plans to Read more…

Qubits 2024: D-Wave’s Steady March to Quantum Success

June 18, 2024

In his opening keynote at D-Wave’s annual Qubits 2024 user meeting, being held in Boston, yesterday and today, CEO Alan Baratz again made the compelling pitch Read more…

Shutterstock_666139696

Argonne’s Rick Stevens on Energy, AI, and a New Kind of Science

June 17, 2024

The world is currently experiencing two of the largest societal upheavals since the beginning of the Industrial Revolution. One is the rapid improvement and imp Read more…

Under The Wire: Nearly HPC News (June 13, 2024)

June 13, 2024

As managing editor of the major global HPC news source, the term "news fire hose" is often mentioned. The analogy is quite correct. In any given week, there are Read more…

Labs Keep Supercomputers Alive for Ten Years as Vendors Pull Support Early

June 12, 2024

Laboratories are running supercomputers for much longer, beyond the typical lifespan, as vendors prematurely deprecate the hardware and stop providing support. Read more…

MLPerf Training 4.0 – Nvidia Still King; Power and LLM Fine Tuning Added

June 12, 2024

There are really two stories packaged in the most recent MLPerf  Training 4.0 results, released today. The first, of course, is the results. Nvidia (currently Read more…

Highlights from GlobusWorld 2024: The Conference for Reimagining Research IT

June 11, 2024

The Globus user conference, now in its 22nd year, brought together over 180 researchers, system administrators, developers, and IT leaders from 55 top research Read more…

Atos Outlines Plans to Get Acquired, and a Path Forward

May 21, 2024

Atos – via its subsidiary Eviden – is the second major supercomputer maker outside of HPE, while others have largely dropped out. The lack of integrators and Atos' financial turmoil have the HPC market worried. If Atos goes under, HPE will be the only major option for building large-scale systems. Read more…

Comparing NVIDIA A100 and NVIDIA L40S: Which GPU is Ideal for AI and Graphics-Intensive Workloads?

October 30, 2023

With long lead times for the NVIDIA H100 and A100 GPUs, many organizations are looking at the new NVIDIA L40S GPU, which it’s a new GPU optimized for AI and g Read more…

Nvidia H100: Are 550,000 GPUs Enough for This Year?

August 17, 2023

The GPU Squeeze continues to place a premium on Nvidia H100 GPUs. In a recent Financial Times article, Nvidia reports that it expects to ship 550,000 of its lat Read more…

Everyone Except Nvidia Forms Ultra Accelerator Link (UALink) Consortium

May 30, 2024

Consider the GPU. An island of SIMD greatness that makes light work of matrix math. Originally designed to rapidly paint dots on a computer monitor, it was then Read more…

Nvidia’s New Blackwell GPU Can Train AI Models with Trillions of Parameters

March 18, 2024

Nvidia's latest and fastest GPU, codenamed Blackwell, is here and will underpin the company's AI plans this year. The chip offers performance improvements from Read more…

Choosing the Right GPU for LLM Inference and Training

December 11, 2023

Accelerating the training and inference processes of deep learning models is crucial for unleashing their true potential and NVIDIA GPUs have emerged as a game- Read more…

Synopsys Eats Ansys: Does HPC Get Indigestion?

February 8, 2024

Recently, it was announced that Synopsys is buying HPC tool developer Ansys. Started in Pittsburgh, Pa., in 1970 as Swanson Analysis Systems, Inc. (SASI) by John Swanson (and eventually renamed), Ansys serves the CAE (Computer Aided Engineering)/multiphysics engineering simulation market. Read more…

Some Reasons Why Aurora Didn’t Take First Place in the Top500 List

May 15, 2024

The makers of the Aurora supercomputer, which is housed at the Argonne National Laboratory, gave some reasons why the system didn't make the top spot on the Top Read more…

Leading Solution Providers

Contributors

AMD MI3000A

How AMD May Get Across the CUDA Moat

October 5, 2023

When discussing GenAI, the term "GPU" almost always enters the conversation and the topic often moves toward performance and access. Interestingly, the word "GPU" is assumed to mean "Nvidia" products. (As an aside, the popular Nvidia hardware used in GenAI are not technically... Read more…

Intel’s Next-gen Falcon Shores Coming Out in Late 2025 

April 30, 2024

It's a long wait for customers hanging on for Intel's next-generation GPU, Falcon Shores, which will be released in late 2025.  "Then we have a rich, a very Read more…

Google Announces Sixth-generation AI Chip, a TPU Called Trillium

May 17, 2024

On Tuesday May 14th, Google announced its sixth-generation TPU (tensor processing unit) called Trillium.  The chip, essentially a TPU v6, is the company's l Read more…

The NASA Black Hole Plunge

May 7, 2024

We have all thought about it. No one has done it, but now, thanks to HPC, we see what it looks like. Hold on to your feet because NASA has released videos of wh Read more…

Nvidia Shipped 3.76 Million Data-center GPUs in 2023, According to Study

June 10, 2024

Nvidia had an explosive 2023 in data-center GPU shipments, which totaled roughly 3.76 million units, according to a study conducted by semiconductor analyst fir Read more…

Q&A with Nvidia’s Chief of DGX Systems on the DGX-GB200 Rack-scale System

March 27, 2024

Pictures of Nvidia's new flagship mega-server, the DGX GB200, on the GTC show floor got favorable reactions on social media for the sheer amount of computing po Read more…

GenAI Having Major Impact on Data Culture, Survey Says

February 21, 2024

While 2023 was the year of GenAI, the adoption rates for GenAI did not match expectations. Most organizations are continuing to invest in GenAI but are yet to Read more…

AMD Clears Up Messy GPU Roadmap, Upgrades Chips Annually

June 3, 2024

In the world of AI, there's a desperate search for an alternative to Nvidia's GPUs, and AMD is stepping up to the plate. AMD detailed its updated GPU roadmap, w Read more…

  • arrow
  • Click Here for More Headlines
  • arrow
HPCwire