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Rolf David

Protonation pathways and metalloenzymes reactivity: Application to superoxide reductase

Published on 28 November 2017

Thesis presented on November 28, 2017

Obtaining targeted molecules under gentle, selective and sustainable conditions is still a major challenge. Artificial metalloenzymes are an important line of enquiry, because by playing, for example, with the second sphere of coordination, it is possible to strongly modify the reactivity of these bio-inspired systems. The development of this chemistry presupposes a thorough knowledge of the different stages of the mechanism of the reaction under study. For this reason, theoretical chemistry is essential to rationalize chemical reactivity, but it still suffers from many shortcomings for the systems we propose to study.
In this work, we study the superoxide reductase, a detoxifying enzyme of the superoxide radical. While many experiments are available detailing some intermediates, the precise mechanism is not well documented. The aim was to implement a complete methodology ranging from the development of specific MM parameters to the study of reactivity by QM/MM metadynamics.
The development of MM parameters for the iron active site allowed its study by MM dynamics giving informations on the conformation of the peptide backbone as well as on the interaction with solvent molecules. Due to the nature of the iron, a QM description of the active site was required using hybrid DFT. QM/MM metadynamics have allowed us to explore reaction pathways and to characterize the compounds formed to obtain the needed activation energies.
This methodology made it possible to understand the native reactivity of the wild form of the SOR, but also to explore the new reactivity of the mutations of the SOR and thus to define the crucial role of the second coordination sphere..

Quantum Chemistry, Reactivity, Metalloenzyme, hybrid methods, metadynamics

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