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Abstract

This dissertation addresses three different aspects of the interdisciplinary research on flavins and flavoproteins, which have been shown to be responsible for a myriad of essential biological, chemical and physical phenomena, from a computational point of view. Sections of the dissertation are outlined below.
Amine Oxidation Mediated by Flavin-dependent Catalysts. The main goal of this part was to probe at the molecular level the catalytic mechanism of the rate-limiting oxidation step of a typical amine demethylation, a common process in diverse biochemical processes. Models were created for the active site of two amine oxidases, lysine-specific-demethylase-1 (LSD1) and N-methyltryptophan oxidase (MTOX) that utilize a covalently or noncovalently bound flavin adenine dinucleotide (FAD) as cofactor. The model systems were studied using quantum mechanics (QM) and hybrid
QM/molecular mechanics (QM/MM) methods, along with classical molecular dynamics (MD) simulations, to identify the most feasible of the proposed pathways for amine oxidation and to explain the role of active-site residues in the reaction.
Photophysics and Photochemistry of Flavin Derivatives. In this part, we focus on the excited-state properties of nine different natural and artificial riboflavin (RF) analogs. We provide an in-depth computational analysis of the photophysics and photodynamics of these flavins using time-dependent density functional theory (TD-DFT) and combined DFT/multi-refence configuration interaction (MRCI) methods. On the basis of this analysis, we identify the most plausible mechanism for the intramolecular charge transfer occurring in a natural RF analog, roseoflavin (RoF). In addition, we assess the potential of eight artificial flavin derivatives to replace wild-type RF in blue-light photoreceptor flavoproteins with the aim of realizing the relevant photoinduced processes with lower
energy input.
Optical Spectroscopy of Flavin Derivatives. Finally, we address the optical spectra of flavin derivatives using computational methods for simulating vibrationally broadened UV-vis spectra that are based on the Franck-Condon (FC) principle. We introduce a new technique that combines the
vertical FC scheme with curvilinear displacements and compare its performance to previous schemes with rectilinear displacements. Thereafter we present a comprehensive benchmark of the performance of most FC-based spectroscopic simulation methods using a carefully chosen set of three flavins with
distinctive structural features.