Context
Dopamine \(\beta \) -monooxygenase (D \(\beta \) M) is an essential enzyme in the organism that regioselectively converts dopamine into R-norepinephrine, the key step of the reaction, studied in this paper, is a hydrogen atom transfer (HAT) from dopamine to a superoxo complex on D \(\beta \) M, forming a hydroperoxo intermediate and dopamine radical. It was found that the formation of a hydrogen bond between dopamine and the D \(\beta \) M catalyst strengthens the substrate-enzyme interaction and facilitates the HAT which takes place selectively to give the desired enantiomeric form of the product. Six reactions leading to the hydroperoxo intermediate were analyzed in detail using theoretical and computational tools in order to identify the most probable reaction mechanism. The reaction force analysis has been used to demonstrate that the nature of the activation energy is mostly structural and largely due to the initial approach of species in order to get closer to each other to facilitate the hydrogen abstraction. On the other hand, the reaction electronic flux revealed that electronic activity driving the reactions is triggered by polarization effects and, in the most probable reaction among the six studied, it takes place in a concerted and non-spontaneous way. Chemical events driving the reaction have been identified and the energy absorbed or delivered by each one was quantified in detail.
Methods
The dopamine and a computational model of the copper superoxo complex on D \(\beta \) M were optimized at B3LYP-D3(BJ)/6-311 G(d,p) level theory in the Gaussian 16 software package. Optimization and IRC calculations were performed in the gas phase and through the PCM solvation model to mimic the protein medium. Non-covalent interactions were plotted using the NCI-plot software.
Graphical abstract
The interaction of dopamine with copper superoxo complex on D \(\beta \) M is studied in order to characterize the mechanism of the hydrogen atom transfer step in the conversion of dopamine into norepinephrine.
