UC Irvine

We investigate the electrostatics, energetics, and dynamics of dendrimer-DNA interactions that mimic protein-DNA complexes as a means to design facilitated mechanisms by which dendrimers can slide and search DNA for targets. By using all-atom molecular dynamics simulations, we calculated the free energy profiles of dendrimer-binding around the DNA via umbrella sampling. We also calculated electrostatic interaction maps in comparison to proteins, as well as the dynamical changes induced by DNA-dendrimer interactions via NMR-measurable order parameters. Our results show that for dendrimers to go around DNA, there is a free-energy barrier of 8.5 kcal/mol from the DNA major groove to DNA minor groove, with a minimum in the major groove. This barrier height makes it unlikely for an all-amine dendrimer to slide along DNA longitudinally, but following a helical path may be possible along the major groove. Comparison of the nonbonded interaction energy and the interaction free-energy profiles reveal a considerable entropic cost as the dendrimer binds to DNA. This is also supported by the mobility patterns obtained from NMR-measurable order parameter values, which show a decreased mobility of the dendrimer N-H bond vectors in the DNA-binding mode.