Frustrated protein and the "perfect fold"

The proteins fold up according to a script written in the diagram of their amino acids. But to work properly, some parts must be ad-lib.

The active sites of enzymes, proteins that accelerate and guide biochemical reactions, make life possible. To do this, their instructions should somewhat contradict the overall structural plan of the protein, according to scientists from Rice University, the University of Buenos Aires and the European Molecular Biology Laboratory in Heidelberg, Germany .

According to the researchers, the evolution has selected some parts of the enzymes as important enough to be able to vigorously move away from the instructions that lead to a folding funnel, which guides proteins into their low-energy functional states. By investigating virtually all known enzymes, the researchers also confirmed the suspicion that additional levels of weaker-frustrated interactions surround and support the catalytic sites themselves.

The detailed theory in Proceedings of the National Academy of Sciences extends the accepted principle of minimal frustration which explains why proteins can smoothly advance linear sequences originally encoded in their DNA to their active three-dimensional globular forms. This principle recognizes that frustration often remains unresolved when the remaining energy conflict serves as a function of the protein's function.

According to Peter Wolynes, of Rice, who laid out the principle in mathematical form more than 20 years ago, energy sceneries of catalytic-catalyzed proteins deserve further badysis, given the importance that evolution badigns them.

"A perfectly folded molecule, as beautiful as it is sculpture, can not do much," he said. "You have to have a protein that, although folded for the most part, still has some frustrated hinges that are incompatible with folding but are necessary to allow the movement required for the chemical reactions."

The frustration at the atomic level is simple to live: it is enough to bring the positive poles of two magnets and to feel how they repel each other. Like magnets, the amino acids of a folding protein attract and repel each other when they (usually) resolve conflicts and eventually form a stable arrangement of contacts.

"Now add a third magnet, and you may experience a frustration you can not get rid of," said co-author Wolynes, who was working with the Buenos Aires team led by biological chemist Diego Ferreiro, former postdoctoral researcher in his group.

The new study shows that frustration among the neighboring amino acids of the enzyme, as in the case of the third magnet, helps to help the frustrated enzyme to remain solid. It remains somewhat unstable but has regions to link with and modify the target molecules.

Obviously, said Wolynes, evolution has priorities that replace the aesthetics of achieving a perfect fold.

The research team examined hundreds of known protein structures by computer and found that whole families of enzymes share active site-like frustration signatures that extend to the second and third layers of amino acids, or shells, around the enzyme.

"The interesting thing we found is that the frustration usually goes beyond the first shell," he said. "This means that there is an awkward but necessary subtlety to the functional constraints that need to properly adjust these three shells."

Wolynes noted that Nobel laureate Frances Arnold and other researchers who study artificial evolution in the laboratory have found signs of prolonged frustration in their efforts to modify enzymes for new reactions.

"Sometimes they specifically changed the active site to catalyze different chemical reactions of natural reactions, but found that the amino acids distant from the active site also needed to be modified for the enzyme to work effectively," he said. declared. "It was not obvious, but the models show that the changes in the second and third shells improve the catalytic capacity of the enzymes.

"Our results were therefore not a total shock, but it's nice to see that prolonged frustration is quite prevalent in nature and is a common theme in all known enzyme clbades," she said. he declared.

This article has been republished from documents provided by Rice University. Note: Content may have changed for length and content. For more information, please contact the cited source.