Reaction mechanism of Ru(II) piano-stool complexes: Umbrella sampling QM/MM MD study

Biologically relevant interactions of piano‐stool ruthenium(II) complexes with ds‐DNA are studied in this article by hybrid quantum mechanics—molecular mechanics (QM/MM) computational technique. The whole reaction mechanism is divided into three phases: (i) hydration of the [RuII(η6‐benzene)(en)Cl]+ complex, (ii) monoadduct formation between the resulting aqua‐Ru(II) complex and N7 position of one of the guanines in the ds‐DNA oligomer, and (iii) formation of the intrastrand Ru(II) bridge (cross‐link) between two adjacent guanines. Free energy profiles of all the reactions are explored by QM/MM MD umbrella sampling approach where the Ru(II) complex and two guanines represent a quantum core, which is described by density functional theory methods. The combined QM/MM scheme is realized by our own software, which was developed to couple several quantum chemical programs (in this study Gaussian 09) and Amber 11 package. Calculated free energy barriers of the both ruthenium hydration and Ru(II)‐N7(G) DNA binding process are in good agreement with experimentally measured rate constants. Then, this method was used to study the possibility of cross‐link formation. One feasible pathway leading to Ru(II) guanine‐guanine cross‐link with synchronous releasing of the benzene ligand is predicted. The cross‐linking is an exergonic process with the energy barrier lower than for the monoadduct reaction of Ru(II) complex with ds‐DNA. © 2014 Wiley Periodicals, Inc. Free energy profiles of interactions of piano‐stool ruthenium(II) complexes with ds‐DNA hexadecamer are explored using the QM/MM‐MD umbrella sampling approach. The Ru(II) complex and two guanines represent a quantum core. The whole reaction mechanism is divided into three phases: the hydration of the complex, the monoadduct formation between the aqua‐Ru(II) complex and the N7 position of one guanine in the ds‐DNA, and the formation of the intrastrand Ru(II) cross‐link between two adjacent guanines.