Side-by-side And End-to-end Attraction Of Double-stranded DNA

Abstract

Genomic DNA is densely packed inside the cell nucleus and viral capsids. Such close packing suggests that electrostatic repulsion between negatively charged DNA in the condensed state is balanced by counterion-induced attraction. Indeed, effective attraction between DNA in high-valence electrolytes has been experimentally demonstrated. Several theoretical models have been proposed to explain DNA attraction, however, specific microscopic mechanisms could not be unequivocally determined. Here, we report sub-microsecond all-atom molecular dynamics (MD) simulations of the effective force between double-stranded DNA in the side-by-side and end-to-end orientations. In a typical simulation, two DNA molecules were placed in an electrolyte solution a certain distance away from one another. An external harmonic potential was applied to keep the distance between the molecules constant, which allowed the effective mean force to be computed directly by averaging over 160 ns-long trajectories. We found that, in a side-by-side conformation, two DNA molecules can form a bond state in the presence of magnesium ions. In the bond state, DNA molecules contact each other via negatively charged phosphate groups, bridged by magnesium ions. For DNA in a monovalent electrolyte, the effective attractive force is too weak to induce DNA condensation in the presence of thermal fluctuations. In the end-to-end orientation, the attraction was found to take place regardless of the electrolyte concentration. The presence of a phosphate group at the 5′-ends of the fragments was found to direct DNA end-to-end self-assembly and produce bound states resembling a continuosus DNA molecule. Our simulations suggest that the end-to-end attraction, rather than being mediated by counterions, is likely caused by hydrophobic and the van der Waals interactions between terminal nucleobases of the fragments.