Effect of a charge-transfer interaction on the catalytic activity of Acyl-CoA dehydrogenase: A theoretical study of the role of oxidized flavin

To examine the role of charge transfer (CT) interactions in the catalytic activity of acyl-CoA dehydrogenase, model systems for the reactant complex of tricyclic or bicyclic models of FAD (Fl(ox)) with the thioenolate portion of acyl-CoA were studied. Singlet excitation energies have been estimated at the TD-B3LYP/ 6-31G(d)//B3LYP/6-31+G(d,p) level of theory. Location and intensity of the charge-transfer band in the UV-absorption spectrum of the thioenolate/Fl(ox) complex depends on the distance between model substrate and isoalloxazine ring and becomes prominent at approximately the van der Waals contact distance. The prereaction complex for hydride transfer from the thioenolate to flavin [fully optimized at B3LYP/6-31 +G(d,p)] possesses a sandwich-like structure with a contact distance of about 3.7 Angstrom between participants and has about 0.7 electrons transferred from the enolate to the flavin. We suggest that the formation of a CT complex in the enzyme has a significant impact on the barrier to a-proton abstraction; it reduces the a-proton affinity of the thioester, thereby lowering the activation energy for the first step in this enzymatic process.