Dynamical properties of DNA-ligand complexes under shear stress: insights from classical molecular dynamics

Nucleic acids are flexible molecules: their dynamical properties play an essential role in molecular recognition and self-assembly. In the biological environment, because of mechanical forces acting at the molecular level, DNA is transiently deformed, cut and resealed, damaged and repaired, and the strands pulled apart and then re-annealed. These unique features make short DNA oligonucleotides promising building blocks in the development of “bottom-up” nano-devices and molecular logic machines.
Single molecule manipulation techniques (Atomic Force Microscopy/ Optical Tweezers) allow detailed investigation of nucleic acids response to the application of controlled mechanical stress. Interpretations of these data in terms of molecular structural changes and dynamical properties call for a collaborative effort between experiments and theoretical/computational modeling.
We have theoretically investigated the dynamical properties a DNA dodecamer and its complex with two different binders (Hoechst 33258 and Ethidium cation) by performing fully atomistic classical Molecular Dynamics (MD) simulations. We focused on the modeling of the so-called overstretching transition occurring when double stranded DNA is subjected to a shear stress until separation of the two strands occurs. The results of our analysis reveal the molecular details of the overstretching dynamics and point out the effects of the binders on the structure and the dynamics of the oligonucleotide under stress. The minor groove binder Hoechst 33258 acts as a zip between the two strands enhancing the lifetime of some base-pairs during the pulling experiment while ethidium cation, which is an intercalator, facilitates the separation of the double helix at high elongations. The understanding of the interactions between the binders and the helix at the molecular level gives insights into the unbinding pathways probed by Single Molecule Force Spectroscopy (SMFS).