Atomistic account of structural and dynamical changes induced by small binders in the double helix of a short DNA

Nucleic acids are flexible molecules and their dynamical properties play a key role in molecular recognition events. Small binders interacting with DNA fragments induce both structural and dynamical changes in the double helix. We study the dynamics of a DNA dodecamer and of its complexes with Hoechst 33258, which is a minor groove binder, and with the ethidium cation, which is an intercalator, by molecular dynamics simulation. The thermodynamics of DNA-drug interaction is evaluated in connection with the structure and the dynamics of the resulting complexes. We identify and characterize the relevant changes in the configurational distribution of the DNA helix and relate them to the corresponding entropic contributions to the binding free energy. The binder Hoechst locks the breathing motion of the minor groove inducing a reduction of the configurational entropy of the helix, which amounts to 20 kcal mol(-1). In contrast, intercalations with the ethidium cation enhance the flexibility of the double helix. We show that the balance between the energy required to deform the helix for the intercalation and the gain in configurational entropy is the origin of cooperativity in the binding of a second ethidium and of anti-cooperativity in the binding of a third one. The results of our study provide an understanding of the relation between structure, dynamics and energetics in the interaction between DNA fragments and small binders, highlighting the role of dynamical changes and consequent variation of the configurational entropy of the DNA double helix for both types of binders.