There were the so-called “voracious enzymes”, able to eat the dirt of a laundry, created for a well-known brand of detergent… In biology, in the whole kingdom of life, enzymes act as accelerators (or catalysers) of chemical reactions (more than 5,000 different ones in total) at work in metabolic process (human digestion, for example). In this huge family, glycosidases are specifically responsible for degrading complex glucoses such as starch or cellulose. Understanding the functioning of theses enzymes is all the more important that it is here a question of… Forcing them to reverse their role: To synthesise glucoses instead of cutting them.

That is the preoccupation of the team of Yves-Henri Sanejouand, director of research at CNRS and head of the group « Conception of proteins in silico » within the Unité de fonctionnalité et ingénierie des protéines (UFIP, Université de Nantes/CNRS).

They carried out their work in link with a team of experimenters, led by Charles Tellier, also director of UFIP.

A major interest for the pharmaceutical industry

“This issue presents a major interest for some industrials, such as pharmaceutical ones“, Yves-Henri Sanejouand explained. “Because the synthesis of these assemblies, for example for designing some anticoagulant drugs, is today a long, complex and above all costly process”.

However, even if experimenters know how to modify a glycosidase for synthesising glucoses, they still have far to go… In particular, because, contrary to what could be thought, the structures of a “synthesising” glycosidase and a “cutting” one are proving to be identical when observed. What are then the phenomena at work?

Curie and Occigen mobilized

For answering this question, the researchers have realised several series of molecular dynamic simulations, in 2015 and 2016, on two GENCI’s supercomputers: Curie, operated by CEA at TGCC near Paris, and Occigen, operated by Cines in Montpellier. They have worked on the basis of the following hypothesis: The action of molecules of water (hydrolyse) producing the break between two glucoses, these molecules would enter the enzyme through specific channels that could be modified for reversing its functioning.

Thanks to nearly 600,000 core hours globally awarded by GENCI, the research team has highlighted not only that molecules of water actually circulated in all studied glycosidases but also that these water chains (or channels) moved differently depending on whether the enzyme cuts or synthesises glucoses.

These simulations, on the order of 500 nanoseconds each, need now to be precisely analysed for an accurate recognition of the way the water channels take.

Several publications, including a these (including that of Benoît David), are under preparation.