A concept to tailor catalytic nucleic acid structures is introduced. The method involves the covalent conjugation of catalytically active metal ion complexes to sequence-specific ligand-binding nucleic acids (aptamers) yielding hybrids termed "nucleoapzymes" that act as enzyme-mimicking nucleic acid based structures. The concentration of the substrate by the aptamer binding site, in close proximity to the metal ion complex catalytic site, models the active site structures of native enzymes and yields catalytic systems. The possibility to tether the catalytic sites to the 3′- or 5′-ends of the aptamer, to internal bases associated with the aptamer sequence, or the feasibility to introduce arbitrary flexible nucleic acid chains between the metal ion complex catalyst and the aptamer binding site provides a rich arsenal of diverse nucleoapzymes for each chemical transformation. The synthesis and characterization of Cu2+-terpyridine nucleoapzymes and of Fe3+-terpyridine nucleoapzymes that catalyze the oxidation of dopamine to aminochrome by H2O2 is presented. One of the Cu2+-terpyridine nucleoapzymes reveals a 60-fold catalytic enhancement in comparison to the separated catalyst/aptamer units. Similarly, one Fe3+-terpyridine nucleoapzyme reveals a 140-fold catalytic enhancement in comparison to the separated catalyst/aptamer units. The different Cu2+-terpyridine nucleoapzymes reveal different activities, dominated by the relative spatial configurations of the catalytic site with respect to the dopamine (substrate) binding site. Molecular dynamics simulations were used to probe the association of the dopamine substrate to the different nucleoapzymes and to rationalize the experimental catalytic performance of the nucleoapzymes in terms of their computed structures. The nucleoapzyme concept bridges homogeneous catalysis with the binding properties of nucleic acids to yield catalysts operating in aqueous media.
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