Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Supercomputers help ORNL researchers identify key molecular switch that controls cell behavior

18.12.2013
If scientists can control cellular functions such as movement and development, they can cripple cells and pathogens that are causing disease in the body.

Supported by National Institutes of Health grants, researchers at Oak Ridge National Laboratory (ORNL), the University of Tennessee (UT), and the UT–ORNL Joint Institute for Computational Sciences (JICS) discovered a molecular “switch” in a receptor that controls cell behavior using detailed molecular dynamics simulations on a computer called Anton built by D. E. Shaw Research in New York City.


Red and blue molecules represent a conformational switch essential to the signaling mechanism of an E. coli chemoreceptor that researchers discovered using computational molecular dynamics simulations. Image credit: Davi Ortega

To study an even larger signaling complex surrounding the switch, the team is expanding these simulations on the 27-petaflop, CPU–GPU machine Titan—the nation’s most powerful supercomputer, managed by the Oak Ridge Leadership Computing Facility at ORNL.

Researchers identified the molecular switch on Anton (which was designed to perform speedy molecular dynamics simulations) by simulating 140,000 atoms that make up the signaling part of the Tsr chemoreceptor that controls motility in E. coli. Like other receptors, Tsr spans the cell membrane, communicating to proteins inside the cell in order to respond to threats or opportunities in the environment.

The results, published in Nature Communications, stand apart from previous research because of the computational power applied to the problem.

“This work exemplifies the growing importance of numerical experiments in biology,” said Jerome Baudry, assistant professor in the UT Biochemistry and Cellular and Molecular Biology Department and the UT–ORNL Center for Molecular Biophysics.

The team led by Baudry and Igor Zhulin, distinguished research and development staff member in the ORNL Computer Science and Mathematics Division, joint professor in the UT Department of Microbiology, and JICS joint faculty member determined that a single pair of phenylalanine amino acids called Phe396 located at the chemoreceptor tip was acting as a receptor switch.

“For decades proteins have been viewed as static molecules, and almost everything we know about them comes from static images, such as those produced with X-ray crystallography,” Zhulin said. “But signaling is a dynamic process, which is difficult to fully understand using only snapshots.”

The Phe396 pair is restless, always flipping 180 degrees back and forth relative to the receptor, but researchers identified a clear pattern.

“It is like a crazy light switch,” Zhulin said. “When you switch it on to light up your room, it occasionally flips down giving you moments of darkness, and when you switch it off to go to sleep, it occasionally goes up flashing.”

When the receptor is in signal-on mode, the switch spends more time in the “on” position. When the receptor is in signal-off mode, the switch spends more time in the “off” position.

“To our knowledge, this is the first time this switch has been described,” said Davi Ortega, lead author and postdoctoral fellow in Zhulin’s lab.

The team, including collaborators at the University of Utah led by John Parkinson, compared thousands of chemoreceptor sequences from all microbial genomes in the Microbial Signal Transduction database available as of August 2012. Remarkably, the Phe396 amino acid was present in all of them, indicating it is likely the switch has existed throughout more than 2 billion years of microbial evolution.

Phenylalanine pairs capable of forming a molecular switch are also present in many other signaling proteins, including receptors in human cells, making it an attractive target for drug design and biotechnology applications.

However, using Anton, researchers were able to simulate only a small part of the chemoreceptor containing the Phe396 pair known as a dimer, meaning two identical molecules. But these two molecules do not work alone.

Dimers are grouped in threes to form larger units of the signaling complex, called trimers of dimers. Researchers expect simulating a trimer next will reveal more about how the Phe396-mediated signal is amplified across neighboring proteins.

But a trimer simulation requires modeling almost 400,000 atoms with increasingly complex physics calculations as the system gets larger. To do so, the group needs a lot of computational capacity.

“Anton is an exceptional machine, but its hardware limitations won’t permit the simulation of such a large system,” Ortega said. “We need Titan.”

Using Titan they ran a preliminary simulation to determine that they would need millions of processing hours on this petaflop machine capable of quadrillions of calculations per second. Titan’s GPUs are highly parallel, hurtling through repetitive calculations such as those modeling the large system of atoms under a vast array of configurations in the trimer simulation.

“With Titan we will begin to see how the signal propagates across chemoreceptors,” Zhulin said. “We think this will start to explain how signals are amplified by these remarkable molecular machines.”

ORNL is managed by UT-Battelle for the Department of Energy’s Office of Science. DOE’s Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, please visit http://science.energy.gov.

Katie Jones | EurekAlert!
Further information:
http://www.ornl.gov
http://www.ornl.gov/ornl/news/news-releases/2013/supercomputers-help-ornl-researchers-identify-key-molecular-switch-that-controls-cell-

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Water - as the underlying driver of the Earth’s carbon cycle

17.01.2017 | Earth Sciences

Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

17.01.2017 | Materials Sciences

Smart homes will “LISTEN” to your voice

17.01.2017 | Architecture and Construction

VideoLinks
B2B-VideoLinks
More VideoLinks >>>