Duocarmycins are a potent class of antitumor agents. Their activity arises by their covalent binding to adenine nucleobases of DNA. We use classical mol. dynamics and hybrid (QM/MM) Car-Parrinello mol. dynamics simulations to study non-covalent and covalent binding of three duocarmycins with different reactivities, namely DSA, DSI and NBOC-DSA. Reactions in water are explored for NBOC-DSA with adenine and simple model reactants. Our calcns. suggest that: (i) Non-covalent drug binding does not significantly perturb the DNA structure. (ii) The exptl. obsd. DNA catalytic power might be due, at least in part, to a polarization of the biomol. scaffold over the drugs. Instead, our calcns. do not support the "shape induced activation" mechanism, in which the conformational properties of the drug play a pivotal role for catalysis (5). (iii) The chem. nature of the drug influences the structure of the drug-DNA adduct, thus affecting the reactivity of the initial complex. (iv) The functional groups of the drugs affect the intrinsic reactivity of the compd. [on SciFinder (R)]