Global and local descriptors of chemical reactivity can be derived from conceptual density functional theory. Their explicit form, however, depends on how the energy is defined as a function of the number of electrons. Within the existing interpolation models, here, the quadratic and the linear energy model were used to derive global descriptors as the electrophilicity and nucleophilicity (defined as the negative of the ionization potential) and local descriptors employing either the corresponding condensed Fukui function in the linear model or the local response of the global descriptor in the quadratic model. The ability of these descriptors to predict the reactivity of molecules with more than one reactive site was first studied on a set of α, β-unsaturated ketones, where experimental rate constants for the nucleophilic attack is known. With the validated descriptors the reactivity of α, β-unsaturated carboxylic compounds with different heteroatoms as α, β-unsaturated thioesters, esters, and amides was addressed as alternative substrates for enzymatic CO 2 fixation.Carbon dioxide fixation involves the reduction of the neutral α, β-unsaturated carboxylic compounds by a nucleophilic attack of a hydride anion from NADPH and the following electrophilic attack by carbon dioxide. It was found that condensed values of the linear Fukui function within the fragment of molecular response approximation describe best the reactivity of α, β-unsaturated ketones. For the two relevant processes involved in CO 2 fixation the amides present the largest reactivity in vacuum and in aqueous solution compared to the esters and thioesters and may, therefore, serve as alternative substrates of carboxylases. K E Y W O R D SFukui function, linear and quadratic energy models, reactivity descriptors, α,β-unsaturated compounds

<div>Global and local descriptors of chemical reactivity can be derived from conceptual density functional theory. Their explicit form, however, depends on how the energy is defined as a function of the number of electrons. Within the existing interpolation models, here, the quadratic and the linear energy model were used to derive global descriptors as the electrophilicity and nucleophilicity (defined as the negative of the ionization potential) and local descriptors employing either the corresponding condensed fukui function in the linear model or the local response of the global descriptor in the quadratic model. The ability of these descriptors to predict the reactivity of molecules with more than one reactive site was first studied on a set of α ,β -unsaturated ketones, where experimental rate constants for the nucleophilic attack is known. With the validated descriptors the reactivity of α ,β -unsaturated carboxylic compounds with different heteroatoms as α ,β -unsaturated thioesters, esters and amides as alternative substrates for the enzymatic CO₂ fixation studied experimentally by Erb <i>et al.</i> was addressed. The carbon dioxide fixation involves the reduction of the neutral α ,β -unsaturated carboxylic compounds by a nucleophilic attack of a hydride anion from NADPH and the following electrophilic attack by carbon dioxide. It was found that condensed values of the linear fukui function within the fragment of molecular response approximation describe best the reactivity of α ,β -unsaturated ketones. For the two relevant processes involved in CO₂ fixation the amides present the largest reactivity in vacuum and in aqueous solution compared to the esters and thioesters and may, therefore, serve as alternative sustrates of carboxylases.</div>

Most CO2 from the atmosphere is assimilated into photosynthetic organisms by the ribulose 1,5-bisphosphate carboxylase-oxygenase (RuBisCO) enzyme as part of the Calvin cycle. Despite its relevance and many efforts in the last few decades, the mechanistic picture of the catalytic CO2 fixation reaction is still under debate. Here, we combine QM/MM molecular dynamics simulations with high-level electronic structure methods and the projector-embedding approach to provide reference values for the activation and reaction free energies of the catalytic CO2 fixation reaction. Our results show that carboxylation is protonation-state-dependent and irreversible, making the reverse reaction (decarboxylation reaction) highly unfavorable. The carbamylated lysine residue, Kcx201, coordinated to the magnesium­(II) cation in the active site plays a central role shuffling protons from and to the substrate, creating the proper reactive enolate species that adds CO2. The emerging microscopic picture that involves several protonation equilibria and the free-energy profile of the CO2 fixation reaction provides insights that may be used in the future to improve enzymatic efficiency in RuBisCO.

<div><div><div><p>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 QM/MM 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 reac- tivity descriptors based on conceptual DFT. 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 changes in 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 to an aqueous solution. Our main result is that the protein en- vironment 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.</p></div></div></div>

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.

Most CO2 from the atmosphere is assimilated in photosynthetic organisms by the ribulose 1,5-bisphosphate carboxylase-oxygenase (RuBisCO) enzyme as part of the Calvin cycle. Despite its relevance and many efforts in the last few decades, the mechanistic picture of the catalytic CO2 fixation reaction is still under debate. Here, we combine QM/MM molecular dynamics simulations with high-level electronic structure methods and the projector-embedding approach to provide reference values for the activation and reaction free energies of the catalytic CO2 fixation reaction. Our results show that carboxylation is protonation state dependent and irreversible, making the back reaction (decarboxylation reaction) highly unfavourable. The carbamylated lysine residue, Kcx201, coordinated to the magnesium (II) cation in the active site plays a central role shuffling protons from and to the substrate creating the proper reactive enolate species that adds CO2. The emerging microscopic picture that involves several protonation equilibria and the free energy profile of the CO2 fixation reaction provides insights that may be used in the future to improve enzymatic efficiency in RuBisCO.

No abstract

Most CO2 from the atmosphere is assimilated in photosynthetic organisms by the ribulose 1,5-bisphosphate carboxylase-oxygenase (RuBisCO) enzyme as part of the Calvin cycle. Despite its relevance and many efforts in the last few decades, the mechanistic picture of the catalytic CO2 fixation reaction is still under debate. Here, we combine QM/MM molecular dynamics simulations with high-level electronic structure methods and the projector-embedding approach to provide reference values for the activation and reaction free energies of the catalytic CO2 fixation reaction. Our results show that carboxylation is protonation state dependent and irreversible, making the back reaction (decarboxylation reaction) highly unfavourable. The carbamylated lysine residue, Kcx201, coordinated to the magnesium (II) cation in the active site plays a central role shuffling protons from and to the substrate creating the proper reactive enolate species that adds CO2. The emerging microscopic picture that involves several protonation equilibria and the free energy profile of the CO2 fixation reaction provides insights that may be used in the future to improve enzymatic efficiency in RuBisCO.