THE ROAD TO LA-LA LAND

August 3, 2001

by Michael Schneider, Pittsburgh Supercomputing Center

If you’ve had surgery, you may recall noticing the brightness of the ceiling lights in the operating room. Next thing you know your eyes peel open and a voice asks, “How are you feeling?” In the meantime, someone has sliced your body open and put it back together.

General anesthesia is one of the wonders of medicine. The ability to induce a deeply unconscious, immobile state makes possible life-saving procedures no one could have imagined 150 years ago, when surgeons were “saw-bones” and tooth extraction or amputation of a limb was excruciating beyond description. The discovery of ether’s anesthetizing effect in the 1840s has led in recent decades to new, safer anesthetics. An estimated 15 million Americans undergo general anesthesia annually. Despite the advances in pharmacology and wide use, however, no one can tell you how anesthetics do what they do.

“General anesthesia has been used for more than a century,” says Pei Tang, a physical chemist and assistant professor of anesthesiology and pharmacology at the University of Pittsburgh School of Medicine (UPSM). “It’s one of the most important tools of medicine, and yet it remains mysterious. Despite years of research, we still don’t understand the molecular mechanism.”

It’s an alluring mystery. What’s known about general anesthetics suggests they are a peculiar class of drugs, with their own way of acting in the body that doesn’t fit the standard model of how drugs work. Understanding the molecular details would likely lead to better anesthetics, with fewer side effects, but perhaps even more importantly it should tell us something about consciousness itself, one of the grandly intriguing questions in science.

An unconsciousness deeper than sleep, general anesthesia involves complete muscle relaxation — the loss of fight or flight response, which persists in sleep — and total amnesia. Arguably the ultimate altered state, it’s like flipping a switch to temporarily turn off the nervous system. Understanding how this happens will increase our feeble knowledge of what it means biochemically to be switched “on” with the self-awareness that may be the essential trait of being human.

Tang is part of a UPSM team that uses a range of techniques to investigate how anesthetics work. In collaboration with Pittsburgh Supercomputing Center scientists Marcela Madrid and Troy Wymore, she has used computational methods to simulate how the drugs interact with the cellular membranes where they have their effect. The results of these studies challenge accepted thinking and offer support for an emerging new hypothesis.

A Tale of Two Theories

In the normal, undrugged state of consciousness, sense perceptions trigger a chain of events that releases electrical signals in the form of ion flow — sodium, calcium, potassium and other ions — through channels in the cell walls, better known to biologists as membranes. General anesthetics appear to exert their effect by changing ion flow through these membrane channels, either slowing it down or speeding it up. Thinking about how this happens falls generally into two schools: the lipid theory and the protein theory.

The lipid theory, the older point of view, says that general anesthetics work by their ability to dissolve in lipids, the fat that forms the cell membrane and seals it against the watery environs inside and outside the cell. This view arose, initially, from finding that the potency of an anesthetic chemical corresponds to how well it dissolves in olive oil. Following from this awareness, some experiments suggest that anesthetics make the lipid more fluid, a structural loosening that relaxes and changes the shape of the channels that control ion flow.

The protein theory is more recent and says, on the other hand, that general anesthetics interact directly with the channels, which are complex proteins, rather than indirectly through the lipids. This idea is closer to the lock-and-key model of how most drugs work, by binding with a specific site on a protein and blocking its interaction with other molecules. This model doesn’t fit well with anesthetics, however, because there’s little structural similarity among different anesthetics, one reason the lipid theory gains adherents. The drug can’t have its effect by acting like a key in a lock, in other words, when there are so many different shapes that work.

Experiments have shown, nevertheless, that a range of anesthetics have the ability to radically slow down flashes of light from a protein called luciferase, which makes the tails of fireflies glow. Luciferase doesn’t exist in cell membranes, so in this case at least, the effect is direct. Still the question is how. Anesthetics are “low-affinity” drugs — they must be administered in relatively high concentration, another indication that they don’t latch on tightly at a specific site like most other drugs, which are high affinity. In experiments with membranes, as opposed to isolated proteins, it’s extremely difficult to test the protein theory because it’s nearly impossible to disentangle direct from indirect action.

For that, computational simulations, which track the atom-by-atom details of the drug-membrane-channel interactions, have the potential to break through the theoretical logjam. “Only new techniques like large-scale simulations,” says Tang, “that permit analysis at or near atomic resolution can test these theories.”

Lipids, Drugs & Protein in a Water Sandwich

Cellular membranes are complex molecular assemblies involving tens of thousands of atoms, and only in recent years has computational capability evolved to make it feasible to simulate these structures. Starting in 1999, as the first step in a staged process, Tang constructed and tested a computational model of a cellular membrane called DMPC (short for dimyristoylphosphatidylcholine).

Lipids are long-chain molecules with one end, the “head-group,” that gets along chemically with water and a tail-end that’s hydrophobic, water avoiding. Cellular membranes are bilayers of these molecules, with head-groups facing outward and inward to meet with water while the tails converge in the hydrophobic interior. Tang built a bilayer of 200 DMPC molecules and added a layer of water on each side, 5,483 water molecules, to realistically represent the chemical environment. Using the NAMD2 molecular dynamics program on PSC’s CRAY T3E, she simulated how this structure, a lipid bilayer in a water sandwich, changes under realistic conditions. The results gave structural parameters for the membrane that agreed well with experimental data.

The next step was to compute the structural details and electronic properties of two frequently used general anesthetics, halothane and sevoflurane. These quantum-theory calculations provide information such as the precise distance and angles between atoms in the drug molecules along with the electronic charges that influence their interaction with other molecules. The results, which again agreed well with experimental data, provided parameters for Tang’s next step: to simulate how anesthetic drugs act within the membrane-channel environment.

With the groundwork in place, Tang used NAMD2 and the CRAY T3E for a simulation that included 10 halothane molecules inside the DMPC membrane, which itself included a protein molecule, gramicidin, as an ion channel through the lipid bilayer. This very large-scale computation included 38,724 atoms and tracked the molecular movements for two nanoseconds (a billionth of a second) with a freeze-frame picture of the system every femtosecond (a millionth of a billionth of a second).

After about 240 hours of processing (on 128 processors), the results show, contrary to accepted understanding, that halothane in the center of the lipid moves away from this hydrophobic environment toward the water. “People have believed that all anesthetics prefer hydrophobic environments,” says Tang. “Even those who support the protein theory thought that anesthetics interacted with hydrophobic cavities in the channel. We found, however, that the halothane always moves away from the center toward the interface between the lipids and water.”

This result supports an emerging hypothesis that bridges between the two competing theories and suggests that general anesthetics act at the channel-water interface. The simulation lends further support to this view by showing that halothane interacts strongly with one of the protein’s amino-acid side-chains (tryptophan), which resides close to the channel. This finding appears to coincide with recent UPSM laboratory work.

To further test the interface hypothesis, Tang looks forward to PSC’s Terascale Computing System. She’d like to simulate other anesthetics and extend simulation time into the millisecond range. She also plans to simulate compounds structurally very similar to anesthetics but that produce no anesthetic effect. These studies, she expects, will help pinpoint the molecular events that lead to general anesthesia. “With these simulations,” says Tang, “I believe we’ll be able to draw some conclusions that will lead us closer to solving this mystery.”

More information, including graphics: http://www.psc.edu/science/tang.html

============================================================

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!

Bill Gropp on ‘Different Approaches to AI’

November 6, 2024

Around this same time last year, I expounded on what the “Future of AI” may entail. A lot has happened in the 12 months since then, including new approaches, new trends and, yes, new complications. A lot of the ne Read more…

Google Cloud Sporting a New Look in HPC and AI Hardware

November 5, 2024

It's raining hardware at Google Cloud, with the company making major upgrades in advance of bringing Nvidia's Blackwell GPUs into its fold next year. The upgrades announced in late October include a preview of its new Read more…

Go (Mountain) West, Quantum Workers! CU, CUbit, and Elevate Quantum Issue Workforce Roadmap

November 5, 2024

Last week the University of Colorado (Boulder), the CUbit Quantum Initiative, and the Elevate Quantum consortium released workforce roadmap for educating and building a quantum workforce. “This roadmap provides a foun Read more…

Collaboration Speeds Complex Chemical Modeling

November 4, 2024

A recent collaboration among researchers from HUN-REN Wigner Research Centre for Physics in Hungary and the Department of Energy's Pacific Northwest National Laboratory (PNNL), along with industry collaborators SandboxAQ Read more…

High-Performance Storage for AI and Analytics Panel

October 31, 2024

When storage is mentioned in an AI or Big Data analytics context, it is assumed to be a high-performance system. In practice, it may not be, and the user eventually learns about scaleable storage as the amounts of data g Read more…

Microsoft Azure & AMD Solution Channel

Join Microsoft Azure and AMD at SC24

Atlanta, Georgia is the place to be this fall as the high-performance computing (HPC) community convenes for Supercomputing 2024. SC24 will bring together an unparalleled mix of scientists, engineers, researchers, educators, programmers, and developers for a week of learning and sharing. Read more…

White House Mulls Expanding AI Chip Export Bans Beyond China

October 31, 2024

The Biden administration is reportedly considering capping sales of advanced artificial intelligence (AI) chips from US-based manufacturers like AMD and Nvidia to certain countries, including those in the Middle East. � Read more…

Bill Gropp on ‘Different Approaches to AI’

November 6, 2024

Around this same time last year, I expounded on what the “Future of AI” may entail. A lot has happened in the 12 months since then, including new approaches Read more…

Shutterstock 1179408610

Google Cloud Sporting a New Look in HPC and AI Hardware

November 5, 2024

It's raining hardware at Google Cloud, with the company making major upgrades in advance of bringing Nvidia's Blackwell GPUs into its fold next year. The upg Read more…

Go (Mountain) West, Quantum Workers! CU, CUbit, and Elevate Quantum Issue Workforce Roadmap

November 5, 2024

Last week the University of Colorado (Boulder), the CUbit Quantum Initiative, and the Elevate Quantum consortium released workforce roadmap for educating and bu Read more…

Collaboration Speeds Complex Chemical Modeling

November 4, 2024

A recent collaboration among researchers from HUN-REN Wigner Research Centre for Physics in Hungary and the Department of Energy's Pacific Northwest National La Read more…

High-Performance Storage for AI and Analytics Panel

October 31, 2024

When storage is mentioned in an AI or Big Data analytics context, it is assumed to be a high-performance system. In practice, it may not be, and the user eventu Read more…

Shutterstock_556401859

Role Reversal: Google Teases Nvidia’s Blackwell as It Softens TPU Rivalry

October 30, 2024

Customers now have access to Google's homegrown hardware -- its Axion CPU and latest Trillium TPU -- in its Cloud service.  At the same time, Google gave custo Read more…

AI Has a Data Problem, Appen Report Says

October 30, 2024

AI may be a priority at American companies, but the difficulty in managing data and obtaining high quality data to train AI models is becoming a bigger hurdle t Read more…

Report from HALO Details Issues Facing HPC-AI Industry

October 28, 2024

Intersect360 Research has released a comprehensive new report concerning the challenges facing the combined fields of high-performance computing (HPC) and artif Read more…

Shutterstock_2176157037

Intel’s Falcon Shores Future Looks Bleak as It Concedes AI Training to GPU Rivals

September 17, 2024

Intel's Falcon Shores future looks bleak as it concedes AI training to GPU rivals On Monday, Intel sent a letter to employees detailing its comeback plan after Read more…

Granite Rapids HPC Benchmarks: I’m Thinking Intel Is Back (Updated)

September 25, 2024

Waiting is the hardest part. In the fall of 2023, HPCwire wrote about the new diverging Xeon processor strategy from Intel. Instead of a on-size-fits all approa Read more…

Ansys Fluent® Adds AMD Instinct™ MI200 and MI300 Acceleration to Power CFD Simulations

September 23, 2024

Ansys Fluent® is well-known in the commercial computational fluid dynamics (CFD) space and is praised for its versatility as a general-purpose solver. Its impr Read more…

xAI Colossus: The Elon Project

September 5, 2024

Elon Musk's xAI cluster, named Colossus (possibly after the 1970 movie about a massive computer that does not end well), has been brought online. Musk recently Read more…

Shutterstock 1024337068

Researchers Benchmark Nvidia’s GH200 Supercomputing Chips

September 4, 2024

Nvidia is putting its GH200 chips in European supercomputers, and researchers are getting their hands on those systems and releasing research papers with perfor 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…

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 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…

Leading Solution Providers

Contributors

IBM Develops New Quantum Benchmarking Tool — Benchpress

September 26, 2024

Benchmarking is an important topic in quantum computing. There’s consensus it’s needed but opinions vary widely on how to go about it. Last week, IBM introd Read more…

Intel Customizing Granite Rapids Server Chips for Nvidia GPUs

September 25, 2024

Intel is now customizing its latest Xeon 6 server chips for use with Nvidia's GPUs that dominate the AI landscape. The chipmaker's new Xeon 6 chips, also called Read more…

Zapata Computing, Early Quantum-AI Software Specialist, Ceases Operations

October 14, 2024

Zapata Computing, which was founded in 2017 as a Harvard spinout specializing in quantum software and later pivoted to an AI focus, is ceasing operations, accor Read more…

Quantum and AI: Navigating the Resource Challenge

September 18, 2024

Rapid advancements in quantum computing are bringing a new era of technological possibilities. However, as quantum technology progresses, there are growing conc Read more…

US Implements Controls on Quantum Computing and other Technologies

September 27, 2024

Yesterday the Commerce Department announced export controls on quantum computing technologies as well as new controls for advanced semiconductors and additive Read more…

Google’s DataGemma Tackles AI Hallucination

September 18, 2024

The rapid evolution of large language models (LLMs) has fueled significant advancement in AI, enabling these systems to analyze text, generate summaries, sugges Read more…

Microsoft, Quantinuum Use Hybrid Workflow to Simulate Catalyst

September 13, 2024

Microsoft and Quantinuum reported the ability to create 12 logical qubits on Quantinuum's H2 trapped ion system this week and also reported using two logical qu Read more…

On Paper, AMD’s New MI355X Makes MI325X Look Pedestrian

October 15, 2024

Advanced Micro Devices has detailed two new GPUs that unambiguously reinforce it as the only legitimate GPU alternative to Nvidia. AMD shared new facts on its n Read more…

  • arrow
  • Click Here for More Headlines
  • arrow
HPCwire