In this thesis, density functional theory (DFT) is employed in the study of two enzymes and two organometallic systems.

First, the natural reaction mechanism, as well as the enantioselective formation of α-hydroxyketones catalysed by two thiamine diphosphate (ThDP)- dependent enzymes, namely benzoylformate decarboxylase (BFDC) and 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylic-acid (SEPHCHC)- synthase (MenD), are investigated. To that end, different cluster models that account for the active sites of the enzymes are used. For BFDC, the calculated natural reaction mechanism clarifies the roles of various active site residues and of the cofactor. Moreover, an unprecedented tricyclic cofactor species is found to be kinetically relevant. The importance of this species is further explored in a second study, in which the relative stabilities of the different ThDP-cofactor states are assessed in different enzymatic and non-enzymatic environments. In the last study of BFDC, the enantioselective carboligation mechanism between the enamine intermediate and two different acceptors, namely benzaldehyde or acetaldehyde, is studied. Moving into MenD, the calculated natural reaction mechanism gives insight into the formation tetrahedral post-decarboxylation intermediate, which has been extensively discussed in the literature. Moreover, the proton source in the keto-enol tautomerization in the second part of the mechanism can also be elucidated. Finally, because MenD can perform 1,4- and 1,2-additions, the factors governing the regioand enantioselectivity of two non-natural reactions are covered.

Next, a Pummerer-like, C-C coupling reaction, is studied, and the calculations show that an unstable open-cubane complex yields considerably lower barriers than the more typically suggested linear complexes. In the last study, a ruthenium-catalysed cyclopropanation reaction is investigated. The calculated free-energy profiles indicate a very intricate scenario in which two cyclopropanation mechanisms and two side-reactions need to be considered. Importantly, one of these side-reactions, i.e. a migratory insertion of the carbene into the C-M bond of the ligand, results in the formation of a new catalyst, and a combined computational-experimental effort elucidates which is the active catalyst for the cyclopropanation reaction.