Reaction Mechanism of Ru(II) Piano-Stool Complexes; Umbrella Sampling QM/MM MD Study

Zdenek Futera, Jaroslav V. Burda

Department of Chemical Physics and Optics, Faculty of Mathematics and Physics, Charles

University, Ke Karlovu 3, 121 16 Prague 2, Czech Republic

Biologically relevant interactions of piano-stool ruthenium(II) complexes with ds-DNA were explored by hybrid QM/MM computational technique. The whole reaction mechanism is considered in three step: hydration of [Ru^II(η⁶-benzene)(en)Cl]⁺, binding of resulting aqua complex to DNA and final intra-strand cross-link formation between two neigboring guanosines. Free energy profiles of all reactions are explored by QM/MM MD umbrella sampling approach where the Ru(II) complex is described by DFT and remaining part by General Amber Force Field (GAFF). For that purpose, our own software was developed, which couples the Gaussian and Amber programs. Calculated free energy barriers of Ru(II) hydration as well as DNA binding process are in good agreement with experimentally measured rate constants. Following this method-justification step, possibility of cross-link formation is investigated and one feasible pathway leading to Ru(II) guanosine-guanosine cross-link with synchronous releasing of the benzene ligand is predicted. The cross-linking is exergonic process with energy barrier lower than for initial binding to DNA.