Atom-Condensed Fukui Function in Condensed Phases and Biological Systems and Its Application to Enzymatic Fixation of Carbon Dioxide

Abstract

Local reactivity descriptors such as atom-condensed Fukui functions are promising computational tools to study chemical reactivity at specific sites within a molecule. Their applications have been mainly focused on isolated molecules in their most stable conformation without considering the effects of the surroundings. Here we propose to combine quantum mechanics/molecular mechanics Born–Oppenheimer molecular dynamics simulations to obtain the microstates (configurations) of a molecular system using different representations of the molecular environment and calculate Boltzmann-weighted atom-condensed local reactivity descriptors based on conceptual density functional theory. Our approach takes the conformational fluctuations of the molecular system and the polarization of its electron density by the environment into account, allowing us to analyze the effect of the molecular environment on reactivity. In this contribution, we apply the method mentioned above to the catalytic fixation of carbon dioxide by crotonyl-CoA carboxylase/reductase and study if the enzyme alters the reactivity of its substrate compared with an aqueous solution. Our main result is that the protein environment activates the substrate by the elimination of solute–solvent hydrogen bonds from aqueous solution in the two elementary steps of the reaction mechanism: the nucleophilic attack of a hydride anion from NADPH on the α,β-unsaturated thioester and the electrophilic attack of carbon dioxide on the formed enolate species.

Carbon Dioxide Fixation in RuBisCO Is Protonation-State-Dependent and Irreversible

“…To study if the enolate species formed by initial proton abstraction from C3 ( Enolate 2 ) presents the correct reactivity on the C2 carbon atom to form the observed product, we carried out QM/MM molecular dynamics simulations combined with reactivity descriptors based on conceptual density functional theory. The most reactive site of the enolate was identified based on atom condensed Fukui functions, which are Boltzmann averaged over all configurations of the enzyme–substrate Michaelis complex . These reactivity descriptors include the polarizing effect of the enzyme on the substrate’s electron density and identify the most nucleophilic site in the substrate as the atom with the maximal value in ⟨ f – ⟩.…”

“…The effect of conformational changes in the active site and the enzymatic environment on the reactivity of the substrate was assessed by our recently introduced Boltzmann weighted atom condensed Fukui function defined as where β = (k B T) -1 , T is the temperature, and k B the Boltzmann constant. f A – ( R 1 , ..., R N ) is the atom condensed Fukui function obtained at one specific configuration of nuclei given by R i .…”