P.I.: Serge Antonczak

Sébastien Fiorucci, Jérôme Golebiowski.

Modeling a metabolon involved in flavonoid biosynthesis

In each living system, the concentration of functional biological entities (e.g. proteins, enzymes, peptides…) is incredibly high. Some transient complex-structures may appear and, depending on the affinity the protagonists exhibit for each other, may subsist during sufficiently long timescales that lead to new functional systems called metabolons. Experiments have demonstrated that some metabolons lie at the vicinity of the membrane. Recent investigations highlight the existence of such a metabolon in the course of flavonoids production in which the successive enzymes remain in interaction. The product of an enzymatic reaction becoming the substrate for the neighbouring enzyme, it only has to “jump” from an active site to the next one, diminishing unnecessary diffusion processes and loss of energy during solvation and desolvation processes, yielding an enhanced catalytic efficiency. Being able to precisely describe the overall architecture of these macromolecular assemblies has become essential for understanding the underlying biological mechanisms and for developing new therapeutic strategies. 4 points have to be described in order to understand the properties of such complex: i) enzymatic reaction characterization, ii) prediction of protein-protein complexes, iii) enzyme/substrate interaction and iv) protein/membrane interaction.

Multi-scale approach

To reach this goal, a multi-scale approach, involving a large board of theoretical methods, has been applied in order to decipher the four different points described above. QM/MM MD simulations are used to characterize the enzymatic mechanism, state-of-the-art docking protocol is applied for the prediction of protein-protein complexes. MD brute force simulations have been applied for enzyme/substrate and protein/membrane interactions.