Fundamental discovery casts enzymes in new light

Nov 08, 2011

Just as a breeze causes leaves, branches and ultimately the tree to move, enzymes moving at the molecular level perform hundreds of chemical processes that have a ripple effect necessary for life. Protein complexes are often viewed as static entities with their biological functions understood in terms of direct interactions, but that isn't the case, as emphasized in a paper published November 8 in the online, open-access journal PLoS Biology. The work shows that the amount of flexibility in a protein may itself be an important feature of enzyme function.

"Our discovery is allowing us to perhaps find the knobs that we can use to improve the catalytic rate of enzymes and perform a host of functions more efficiently," said author Pratul Agarwal, from Oak Ridge National Laboratory.

Making this discovery possible was ORNL's supercomputer, Jaguar, which allowed Agarwal and co-author Arvind Ramanathan to investigate a large number of enzymes at the . The researchers found that enzymes have similar flexibility features that are entirely preserved from the smallest —bacteria—to complex life forms, including humans.

"If something is important for function, then it will be present in the protein performing the same function across different species," Agarwal said. "For example, regardless of which company makes a car, they all have wheels and brakes." Similarly, scientists have known for decades that certain aspects of protein sequence and some structural features of the enzyme are also preserved because of their important function. Agarwal and Ramanathan now believe the same is true for enzyme flexibility: it's conserved, independent of sequence and structure.

"The importance of the structure of enzymes has been known for more than 100 years, but only recently have we started to understand that the internal motions may be the missing piece of the puzzle to understand how enzymes work," Agarwal said. "If we think of the tree as the model, the protein moves at the molecular level with the side-chain and residues being the leaves and the protein backbone being the entire stem."

This research builds on previous work in which Agarwal identified a network of protein vibrations in the Cyclphilin A, which is involved in many biological reactions, including the AIDS-causing virus HIV-1.

While Agarwal sees this research perhaps leading to medicines able to target hard to cure diseases such as AIDS, he is also excited about its energy applications, specifically in the area of cellulosic ethanol. Highly efficient enzymes could bring down the cost of biofuels, making them a more attractive option.

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More information: Ramanathan A, Agarwal PK (2011) Evolutionarily Conserved Linkage between Enzyme Fold, Flexibility, and Catalysis. PLoS Biol 9(11): e1001193. doi:10.1371/journal.pbio.1001193

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nanotech_republika_pl
2.5 / 5 (2) Nov 08, 2011
We won't get many of the features of the cell if we can't model on a computer the whole cell at the atomic level. Yes, that's extremely difficult and we may need to wait for a long time for a faster computer (maybe a quantum computer) but that's what it takes. And it is only way to understand the cell.

BTW, I think that we will be able to model the brain successfully before we model liver or pancreas. The brain will probably need a model at synapse level (to show how the inter-neuronal signals are interacting), but an organ like liver, will need a model at atomic level.
hush1
1 / 5 (1) Nov 09, 2011
"For example, regardless of which company makes a car, they all have wheels and brakes." - Agarwal


The wording "fundamental discovery" is incorrect. Use other wording.

Regardless of which woman gives birth to a child, all newborns have mouths, ears, vocal cords and brains.

What can possibly give rise to mouths, ears, vocal cords and brains?
Most will say evolution. They are wrong.
For without sound there is no evolution.
HannesAlfven
1 / 5 (1) Nov 09, 2011
Re: "We won't get many of the features of the cell if we can't model on a computer the whole cell at the atomic level. Yes, that's extremely difficult and we may need to wait for a long time for a faster computer (maybe a quantum computer) but that's what it takes. And it is only way to understand the cell."

This is simply untrue. I read Gerald Pollack's "Cells, Gels and the Engines of Life", and I feel I have a very strong understanding of how the living cell works. The cytoplasm is -- simply put -- a gel. Discard the thought-experiments of channels and pumps, and shift the functionality to the cytoplasm, which behaves as a gel. And there you have it: A revolution in medicine.

Also, it is quite ironic that you point to the need for a quantum computer, because proteins structure water in a manner that is quantum coherent. In other words, the human body IS a quantum computer. And we will in the future create our own quantum machines with gels.
nanotech_republika_pl
not rated yet Nov 11, 2011
@HannesAlfen. Sorry I have not read the book. (Some reviews state that his book is basically spreading disinformation.)

What I had in mind, for example, was a lecture like this
http://www.uctv.t...ID=16423
where this researcher from Stanford is showing their work in modeling bacteria. For example, yes, you have a gel inside a cell, but the ions/atoms/molecules are not randomly distributed in that gel, but have very specific location as in huge molecular machine. You have to make a model as big as this to start grasping the function of the whole mechanism. Yes, it is like an alien engineering. The cell looks like nothing, gels and fibers, but it is more advanced than what we can model right now.
nanotech_republika_pl
not rated yet Nov 11, 2011
Another example is a look at the current science on 3d structure of the DNA inside a cell nucleus. The parts of DNA can not be looked at as just linear molecule but as a very complicated 3 dimensional dance of that molecule.
http://www.scient...a-genome
Callippo
not rated yet Nov 11, 2011
..Fundamental discovery casts enzymes in new light... Protein complexes are often viewed as static entities with their biological functions understood in terms of direct interactions, but that isn't the case...
So we should give the scientific priority of this discovery to the author of this animation...

http://www.youtub...pxe6sPwI

Everyone who dealt with biochemistry a single week knows pretty well, the conformation changes of enzymes (i.e. the induced fit mode) are crucial for their function.