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

OAK RIDGE, Tenn., Dec. 17, 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 UTORNL 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. To study an even larger signaling complex surrounding the switch, the team is expanding these simulations on the 27-petaflop, CPUGPU machine Titanthe 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 UTORNL 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."


Contact: Katie Jones
DOE/Oak Ridge National Laboratory

Related medicine news :

1. Iowa VP for Research addresses next-generation supercomputers at congressional hearing
2. Feinstein Institute researchers show a genetic overlap in schizophrenia and cognitive ability
3. Minorities health would benefit most from beverage sugar tax, UCSF researchers report
4. Wake Forest Baptist researchers study alcohol addiction using optogenetics
5. Researchers discover common cell wall component in Chlamydia bacteria
6. Researchers at Mount Sinai Say a New Strain of Bird Flu Packs a Punch Even After It Becomes Resistant to Drugs
7. OHSU researchers develop new drug approach that could lead to cures for wide range of diseases
8. Keep on exercising, researchers advise older breast cancer survivors
9. CU researchers may have discovered a plan to disable Menieres disease
10. Norwegian brain researchers share Horwitz prize
11. RI researchers validate tool for pain assessment in patients following cardiac surgery
Post Your Comments:
Related Image:
Supercomputers help ORNL researchers identify key molecular switch that controls cell behavior
(Date:12/1/2015)... ... December 01, 2015 , ... ... must mark the film for accurate interpretation by the radiologist. The marking utensils ... inventor from Sacramento, Calif., has found a way to alleviate this problem. , ...
(Date:12/1/2015)... ... December 01, 2015 , ... Visage accelerates mobile ... wholly owned subsidiary of Pro Medicus Ltd. (ASX: PME), has announced they are ... of North America (RSNA) 2015 annual meeting through December 3 in Chicago, Illinois, ...
(Date:12/1/2015)... , ... December 01, 2015 , ... ... it has been selected as a finalist in this year’s Fierce Innovation Awards: ... Next IT Healthcare was recognized as a finalist in the category of Digital ...
(Date:12/1/2015)... ... December 01, 2015 , ... Lutronic, a leading innovator of aesthetic and ... to the devices for sale in the United States. Clarity is a Superior ... nm Nd:YAG lasers, into a single platform that is easy to own and operate. ...
(Date:12/1/2015)... ... December 01, 2015 , ... ... Effective Post-Affiliation Integration ,” addresses a main “pain point” for merging or aligning ... results, once a deal is signed. This quick-read guidance suggests that failing ...
Breaking Medicine News(10 mins):
(Date:12/1/2015)... , Dec. 1, 2015  Athletic apparel ... founder have agreed to pay $1.35 million to ... advertised the company,s copper-infused compression clothing would relieve ... arthritis and other diseases. Tommie ... requires the company and its founder and chairman ...
(Date:12/1/2015)... de diciembre de 2015  AccuTEC Blades, ... de precisión, develó hoy un nuevo logo ... marca. El nuevo logo destaca la experiencia ... ingeniería de productos con cuchillas donde "el ... --> ...
(Date:12/1/2015)... --> --> ... Acid Labeling Market by Product (Reagents & Kits, Services), ... Vitro Transcription, Reverse Transcription, End Labeling), by Region - ... market is expected to reach USD 1,925.7 Million by ... a CAGR of 8.65%. Browse 77 market ...
Breaking Medicine Technology: