Molecular Recognition Routes Of DNA By Anticancer Ligands: Mechanisms and Free Energies Explored Via Molecular Dynamics Simulations

Molecular recognition of the DNA minor groove is a multi-route process which can involve many steps before the formation of the most stable adduct. In particular, many studies have pointed out the importance of events like sliding along the groove and dissociation (which is a relevant step in the translocation among different sequences) for the affinity and the specificity of minor groove binders. In this contribution we present our recent work on the subject. Umbrella sampling and metadynamics were used to characterize mechanisms and free energy profiles of molecular recognition routes by the antitumoral agents anthramycin, duocarmycin and distamycin. Our results are in very good agreement with the available experimental data, and provide insights on the influence of factors like size, charge and flexibility on the molecular recognition process.