Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Are First To Simulate The Binding Of Molecules To A Protein

01.07.2008
You may not know what it is, but you burn more than your body weight of it every day. Adenosine triphosphate (ATP), a tiny molecule that packs a powerful punch, is the primary energy source for most of your cellular functions.

Now researchers at the University of Illinois have identified a key step in the cellular recycling of ATP that allows your body to produce enough of it to survive. Without this cycling of ATP and its low-energy counterpart, adenosine diphosphate (ADP), into and out of the mitochondrion, where ADP is converted into ATP, life as we know it would end.

Researchers have for the first time simulated the binding of ADP to a carrier protein lodged in the inner membrane of the mitochondrion. It is the first simulation of the binding of a molecule to a protein. Their findings appear this week in Proceedings of the National Academy of Sciences.

As its name indicates, ATP contains three phosphate groups. The energy produced when one of these groups is detached from the molecule drives many chemical reactions in the cell. This process also yields ADP, which must go through the ADP/ATP carrier (AAC) to get into the mitochondrion to be converted back into ATP.

... more about:
»ADP »ATP »Membrane »Tajkhorshid »angstrom »binding »mitochondrion

The AAC acts a lot like a revolving door: For each molecule of ADP going into the mitochondrion, one ATP gets booted out. These two activities are not simultaneous, however. The carrier is either shuttling ADP into the mitochondrion or ejecting ATP into the wider environment of the cell, where it can be put to use.

“The carrier is a reversible machine,” said biochemistry professor Emad Tajkhorshid, who led the study which was conducted by biophysics graduate student Yi Wang. “Both ATP and ADP can bind to it and make it to the other side using this transporter.”

Previous studies used X-ray crystallography to determine the three-dimensional structure of the carrier when it was ready to accept a molecule of ADP.

In the new analysis, the researchers developed a computer simulation of the interaction of a single molecule of ADP with the carrier protein. Thanks to better simulation software and larger and more sophisticated computer arrays than were available for previous studies, this simulation tracked the process by which ADP is drawn into the carrier. It also showed how ADP orients itself as it travels to the site where it binds to the carrier.

In the simulation, the researchers observed for the first time that ADP disrupts several ionic bonds, called salt bridges, when it binds to the carrier protein. Breaking the salt bridges allows the protein to open – in effect unlocking the door that otherwise blocks ADP’s route into the mitochondrion.

The simulation included every atom of the carrier protein and ADP, as well as all of the membrane lipids and water molecules that make up their immediate environment – more than 100,000 atoms in all. It tracked the interaction over a period of 0.1 microseconds, an order of magnitude longer than what had been possible before.

“Until two years ago 10 nanoseconds was really pushing it,” Tajkhorshid said. “Now we are reaching the sub-microsecond regime, and that’s why we are seeing more biologically relevant events in our simulations.”

The longer time frame meant that the researchers did not need to manipulate the interaction between the molecules. They simply positioned the ADP at the mouth of the carrier protein, some 25 angstroms from the site where they knew it was meant to bind. (An angstrom is one ten-millionth of a meter. Most molecular binding interactions occur at less than 6 or 7 angstroms.) They even placed the ADP upside-down at the mouth of the protein carrier and saw it flip into an orientation that allowed it to bind to the carrier.

The identified binding pocket for ADP explained a lot of known experimental data, and revealed an unusual feature of the carrier protein: Its binding site and the entryway leading to it had an extremely positive electrical charge.

It had a much greater positive charge than any known protein transporter.

This positive charge appears to serve two functions, Tajkhorshid said. First, it allows the protein carrier itself to nestle tightly in the mitochondrial membrane, which contains a lot of negatively charged lipids. Second, it strongly attracts ADP, which carries a negative charge. More interestingly, through a bioinformatics analysis the researchers show that this unusual electrostatic feature is common to all mitochondrial carriers.

Other negatively charged ions can enter the carrier, Tajkhorshid said, but only a molecule with at least two phosphate groups can disrupt the salt bridges to activate it.

This simulation marks the first time that researchers have been able to describe in molecular detail how a protein binds to the molecule that activates it, Tajkhorshid said.

The findings shed light on a fundamental physiological process, he said.

“Any time you move anything in your body, you use ATP,” he said. “Many enzymatic reactions also require ATP. In the central nervous system, the transport of hormones, neurotransmitters or other molecules, these are all ATP-dependent.”

“It has been estimated that you burn more than your body weight in ATP every day,” he said. “So that’s how much ATP you have to carry across the inner mitochondrial membrane every day – through this guy.”

Tajkhorshid is also a professor of pharmacology in the College of Medicine and an affiliate of the Beckman Institute and the Center for Biophysics and Computational Biology in the College of Liberal Arts and Sciences.

Diana Yates | University of Illinois
Further information:
http://www.uiuc.edu

Further reports about: ADP ATP Membrane Tajkhorshid angstrom binding mitochondrion

More articles from Life Sciences:

nachricht Warming ponds could accelerate climate change
21.02.2017 | University of Exeter

nachricht An alternative to opioids? Compound from marine snail is potent pain reliever
21.02.2017 | University of Utah

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Impacts of mass coral die-off on Indian Ocean reefs revealed

21.02.2017 | Earth Sciences

Novel breast tomosynthesis technique reduces screening recall rate

21.02.2017 | Medical Engineering

Use your Voice – and Smart Homes will “LISTEN”

21.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>