Enzymatic reactions play a fundamental role in biochemical processes, and the study of their mechanisms is of significant interest in biochemistry and computational biology. Understanding the intricate details of these reactions is crucial for gaining insights into enzymatic activity and for developing applications in biotechnology and drug design. Among enzymatic processes, hydride transfer reactions are of particular importance due to their involvement in numerous metabolic pathways. These reactions, often catalyzed by enzymes like NAD(P)H-dependent oxidoreductases, 1,2 play a vital role in maintaining cellular energy balance and enabling complex biochemical transformations. Their mechanisms have inspired the design of new biomimetic compounds with potential applications in green chemistry and drug manufacturing. Possibly the most clear example of exploiting hydride transfer reac-with a particular focus on their use in enzymatic systems. Addressing DFTB3 limitations often involves re-parametrizing the repulsive potentials (RPs). In the density functional tight binding (DFTB) theory, the RPs hold a critical role, encompassing necessary corrections to faithfully reproduce target DFT results. Serving as a key adjustable parameter, RPs have been generated using several methods to better reproduce chemical properties, with recent advancements incorporating machine learning techniques. In this study, our goal was to create a new parameterization of RPs tailored for describing hydride transfer reactions, with a potential application to NAD(P)H-dependent oxidoreductases. To the best of our knowledge, there is no systematic study showing the performance of DFTB3 for hydride transfer reactions in enzymatic systems. We selected Crotonyl-CoA Carboxylase/Reductase (Ccr), a unique enzyme class within the medium chain dehydrogenase/reductase superfamily, as our model system. Ccr is one of the most efficient CO 2 -fixing enzymes and has already been included in synthetic CO 2 fixation pathways. Ccr catalyzes the reductive carboxylation of the substrate crotonyl-CoA to form the carboxylated product (2S)-ethylmalonyl-CoA as shown in Figure . Upon absence of CO 2 in the active site, a reduced side product can be formed which would cause reduction in catalytic efficiency. After the initial hydride transfer step and formation of an enolate intermediate, the enzyme can promote the formation of a covalent adduct (C2 adduct). The latter has been proposed to enhance catalytic efficiency by "storing" the reactive enolate in a more stable intermediate. This study aims to improve the accuracy and applicability of DFTB3 for investigating enzymatic hydride transfer reactions, with a focus on Ccr's catalytic process. The proposed modifications hold the potential to be applied to a wide range of hydride transfer reactions.