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 Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory

nachricht How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>