Enzymatic and bioinspired iron oxidation chemistry: a computational study
- Autores: Lorenzo D'Amore
- Directores de la Tesis: Marcel Swart (dir. tes.), Sílvia Osuna Oliveras (codir. tes.)
- Lectura: En la Universitat de Girona ( España ) en 2021
- Idioma: español
- Tribunal Calificador de la Tesis: Jean-Didier Maréchal (presid.), Anna Company Casadevall (secret.), Vera Krewald (voc.)
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
The oxidative activation of C(sp3)–H bonds under ambient conditions represents a challenge to modern chemistry, nevertheless it is commonly operated in Nature by various oxygenases in key metabolic transformation and biological synthesis. In these enzymes, pre-organized active sites containing powerful electrophilic high-valent heme and non-heme iron-oxo intermediates are capable of stabilizing the transition state, thereby enhancing the reaction rate. In this regard, the spin state and metal coordination are pivotal, determining whether a reaction channel with lower (or higher) activation barrier is operative. On the other hand, besides ordered pockets, enzymes are inherently dynamic and their function is usually connected to accessible conformational states that can be sampled in solution. Laboratory evolution can alter enzymes conformational dynamics by modifying the natural amino acid sequence, populating active states which lead to enhanced catalytic traits or even enable novel functions. However, enzyme engineering can also profoundly impact evolvability, since the phenotypic consequences of sequence mutagenesis may ultimately depend upon the genetic background, which is best know as epistasis.
This thesis presents a computational investigation of the C–H oxidative hydroxylation catalysed by both P450 enzymes and biologically inspired non-heme iron-oxo complexes, and includes inherently orthogonal aspects owing to the wide range of sizes and features of the systems studied, embracing the intrinsic chemical reactivity of C–H activation, as well as conformational dynamics, epistasis and their implications on the catalytic traits of laboratory-evolved P450-BM3 monooxygenase mutants.
