ABSTRACT
This study investigates the factors modulating the reactivity of 5'-deoxyadenosyl (5'dAdoË) radical, a potent hydrogen atom abstractor that forms in the active sites of radical SAM enzymes and that otherwise undergoes a rapid self-decay in aqueous solution. Here, we compare hydrogen atom abstraction (HAA) reactions between native substrates of radical SAM enzymes and 5'dAdoË in aqueous solution and in two enzymatic microenvironments. With that we reveal that HAA efficiency of 5'dAdoË is due to (i) the in situ formation of 5'dAdoË in a pre-ordered complex with a substrate, which attenuates the unfavorable effect of substrate:5'dAdoË complex formation, and (ii) the prevention of the conformational changes associated with self-decay by a tight active-site cavity. The enzymatic cavity, however, does not have a strong effect on the HAA activity of 5'dAdoË. Thus, we performed an analysis of in-water HAA performed by 5'dAdoË based on a three-component thermodynamic model incorporating the diagonal effect of the free energy of reaction, and the off-diagonal effect of asynchronicity and frustration. To this aim, we took advantage of the straightforward relationship between the off-diagonal thermodynamic effects and the electronic-structure descriptor - the redistribution of charge between the reactants during the reaction. It allows to access HAA-competent redox and acidobasic properties of 5'dAdoË that are otherwise unavailable due to its instability upon one-electron reduction and protonation. The results show that all reactions feature a favourable thermodynamic driving force and tunneling, the latter of which lowers systematically barriers by â¼2 kcal mol-1. In addition, most of the reactions experience a favourable off-diagonal thermodynamic contribution. In HAA reactions, 5'dAdoË acts as a weak oxidant as well as a base, also 5'dAdoË-promoted HAA reactions proceed with a quite low degree of asynchronicity of proton and electron transfer. Finally, the study elucidates the crucial and dual role of asynchronicity. It directly lowers the barrier as a part of the off-diagonal thermodynamic contribution, but also indirectly increases the non-thermodynamic part of the barrier by presumably controlling the adiabatic coupling between proton and electron transfer. The latter signals that the reaction proceeds as a hydrogen atom transfer rather than a proton-coupled electron transfer.
Subject(s)
Thermodynamics , Free Radicals/chemistry , S-Adenosylmethionine/chemistry , S-Adenosylmethionine/metabolism , Deoxyadenosines/chemistry , Hydrogen/chemistry , Catalytic Domain , Water/chemistryABSTRACT
Here, we demonstrate that the relationship between reactivity and thermodynamics in radical ligand transfer chemistry can be understood if this chemistry is dissected as concerted ion-electron transfer (cIET). Namely, we investigate radical ligand transfer reactions from the perspective of thermodynamic contributions to the reaction barrier: the diagonal effect of the free energy of the reaction, and the off-diagonal effect resulting from asynchronicity and frustration, which we originally derived from the thermodynamic cycle for concerted proton-electron transfer (cPET). This study on the OH transfer reaction shows that the three-component thermodynamic model goes beyond cPET chemistry, successfully capturing the changes in radical ligand transfer reactivity in a series of model FeIII-OHâ¯(diflouro)cyclohexadienyl systems. We also reveal the decisive role of the off-diagonal thermodynamics in determining the reaction mechanism. Two possible OH transfer mechanisms, in which electron transfer is coupled with either OH- and OH+ transfer, are associated with two competing thermodynamic cycles. Consequently, the operative mechanism is dictated by the cycle yielding a more favorable off-diagonal effect on the barrier. In line with this thermodynamic link to the mechanism, the transferred OH group in OH-/electron transfer retains its anionic character and slightly changes its volume in going from the reactant to the transition state. In contrast, OH+/electron transfer develops an electron deficiency on OH, which is evidenced by an increase in charge and a simultaneous decrease in volume. In addition, the observations in the study suggest that an OH+/electron transfer reaction can be classified as an adiabatic radical transfer, and the OH-/electron transfer reaction as a less adiabatic ion-coupled electron transfer.