In order to model the C–H bond activation step in ribonucleotide reductases the hydrogen atom abstraction reaction from cis-tetrahydrofuran-2,3-diol (7) by methylthiyl (8) radical has been studied with theoretical methods. In order to identify an appropriate theoretical method for this system, the hydrogen transfer reaction between radical 8 and methanol (9) to give methanol radical (10) and methyl thiol (11) has been studied at several different levels of theory. While the reaction energy for this process is predicted equally well by the Becke3LYP and BHandHLYP hybrid functional methods, the reaction barrier is predicted to be significantly lower by the former. Compared to results obtained at CCSD(T)/cc-pVTZ level the BHandHLYP functional is better suited for the calculation of activation barriers for hydrogen abstraction reactions. This latter method was subsequently used to study the reaction of radical 8 with cis-tetrahydrofuran-2,3-diol 7 in the absence and in the presence of additional functional groups (acetate and acetamide) as models for the substrate reaction of class I ribonucleotide reductases (RNRs). The reaction barrier is lowest in those systems, in which acetate forms a double hydrogen bonded complex with the hydroxy groups of diol 7
(+8.2 kcal mol−1) and increases somewhat for side-on complexes between substrate 7 and acetate featuring only one hydrogen bond (+10.5 kcal mol−1). The barrier reduction of 6.5 kcal mol−1 obtained through complexation of diol 7 with acetate appears to be due to the formation of short strong hydrogen bonds in the transition. These effects can also be found in reactions of thiyl radical 8 with complexes of diol 7 with acetamide, but to a much smaller extent. The lowest reaction barrier is in this case calculated for the side-on complex (+11.2 kcal mol−1), while the bridging orientation between diol 7 and acetamide leads to a reaction barrier (+13.4) that is only slightly lower than that for the uncatalyzed process (+14.7 kcal mol−1). With respect to the structure of the active site of the RNR R1 subunit, only the side-on complexes appear to be relevant for the enzyme-catalyzed process. Under this condition the influence of the E441 side chain and thus the impact of the E441Q mutation in the initial C–H bond activation step will be rather small.
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