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Today, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than 1 million visitors each month. The field of early embryology has grown to include the identification of the stem cell as not only critical to organogenesis in the embryo, but equally critical to organ function and repair in the adult human. The identification and understanding of genetic malfunction, inflammatory responses, and the progression in chronic disease, begins with a grounding in primary cellular and systemic functions manifested in the study of the early embryo.

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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
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Home | Pregnancy Timeline | News Alerts |News Archive Dec 19, 2013

 


Red and blue molecules represent an essential switch to the signaling mechanism of an E. coli.
Researchers discovered the switch using computational molecular dynamics simulations.

Image credit: Davi Ortega (hi-res image)







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Supercomputers identify switch controlling cell

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), together have discovered a molecular “switch” in a receptor that controls cell behavior.

Using detailed molecular dynamic simulations on a computer called Anton — built by D. E. Shaw Research in New York City — the team is expanding these simulations on a 27-petaflop, CPU–GPU machine called Titan — the nation’s most powerful supercomputer, managed by the Oak Ridge Leadership Computing Facility at ORNL.


Researchers identified the molecular switch using 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.”

Jerome Baudry, assistant professor, UT Biochemistry and Cellular and Molecular Biology Department, 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,

“But signaling is a dynamic process, which is difficult to fully understand using only snapshots.”

Igor Zhulin, ORNL Computer Science and Mathematics Division, professor, UT–ORNL Joint Institute for Computational Sciences


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

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.


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

Igor Zhulin


“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 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 lots 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 adds. “We think this will start to explain how signals are amplified by these remarkable molecular machines.”

Abstract
Bacterial chemoreceptors are widely used as a model system for elucidating the molecular mechanisms of transmembrane signalling and have provided a detailed understanding of how ligand binding by the receptor modulates the activity of its associated kinase CheA. However, the mechanisms by which conformational signals move between signalling elements within a receptor dimer and how they control kinase activity remain unknown. Here, using long molecular dynamics simulations, we show that the kinase-activating cytoplasmic tip of the chemoreceptor fluctuates between two stable conformations in a signal-dependent manner. A highly conserved residue, Phe396, appears to serve as the conformational switch, because flipping of the stacked aromatic rings of an interacting F396-F396′ pair in the receptor homodimer takes place concomitantly with the signal-related conformational changes. We suggest that interacting aromatic residues, which are common stabilizers of protein tertiary structure, might serve as rotameric molecular switches in other biological processes as well.


Authors:
Davi R. Ortega, Chen Yang, Peter Ames, Jerome Baudry, John S. Parkinson & Igor B. Zhulin

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.