Attractive hydration forces in DNA-dendrimer interactions on the nanometer scale

Abstract

The energetic contribution of attractive hydration forces arising from water ordering is an interesting but often neglected aspect of macromolecular interactions. Ordering effects of water can bring about cooperativity in many intermolecular transactions, in both the short and long range. Given its high charge density, this is of particular importance for DNA. For instance, in nanotechnology, highly charged dendrimers are used for DNA compaction and transfection. Hypothesizing that water ordering and hydration forces should be maximal for DNA complexes that show charge complementarity (positive-negative), we present here an analysis of water ordering from molecular dynamics simulations and free energy calculations of the interaction between DNA and a nanoparticle with a high positive charge density. Our results indicate not only that complexation of the dendrimer with DNA affects the local water structure but also that ordered water molecules facilitate long-range interactions between the molecules. This contributes significantly to the free energy of binding of dendrimers to DNA and extends the interaction well beyond the electrostatic range of the DNA. Such water effects are of potentially substantial importance in cases when molecules appear to recognize each other across sizable distances, or for which kinetic rates are too fast to be due to pure diffusion. Our results are in good agreement with experiments on the role of solvent in DNA condensation by multivalent cations and exemplify a microscopic realization of mean-field phenomenological theories for hydration forces between mesoscopic surfaces.

Figure 1

Starting structures for the dendrimer-DNA systems at 50 Å. (A) All-amine terminated dendrimer with charge +32; (B) Dendrimer with half amine and half acetamide terminations (charge +16). Amine terminations are highlighted in red, acetamide in blue. Close-up of the chemical structure of the core of the PAMAM dendrimer and one branching iteration shown in-between. (C) Potentials of mean force for the systems as a function of the biased reaction coordinate, the center-to-center distance between the dendrimer and DNA. (D) Potentials of mean force as a function of the minimum distance (edge-to-edge) between the dendrimer and DNA.

Figure 2

(A) Electrostatic interaction energy between the dendrimer and DNA as a function of distance. The energy decreases roughly as a function of distance squared (black lines). The total electrostatic energy change for the all-amine dendrimer from 52 to 17 Å is −12,323 kcal/mol, roughly twice the change for the mixed termination dendrimer, −6,216 kcal/mol. (B) Correlation of the free energy of the interaction with the electrostatic interaction energy between DNA and each of the two dendrimers (color coding same as in (A)). For all-amine dendrimer, correlation is roughly linear initially (for the first 9 kcal/mol of free energy). Ensuing, there is a large vertical jump in free energy at long distances (3.4 kcal/mol) that does not correlate with the electrostatic energy. The correlation for the mixed termination dendrimer is linear as well, with approximately the same slope as the first part of the all-amine dendrimer correlation, and a decorrelation/smaller jump in free energy at large distances.

Figure 3

Top view down the DNA helical axis with contour plots of solvent-site dipole moments for (A) all-amine terminated (+32 charge) dendrimer and (B) amine-acetamide terminated (+16 charge) dendrimer; position of dendrimer and DNA marked by white arrows. Significant polarization (bright red-orange) of waters between the dendrimer and DNA are seen at distances of 40 to 60 Å for the all-amine terminated dendrimer only.

Figure 4

Sites of ordered waters. Red arrows represent electrical dipole moment vectors greater than 2 Debye for (A) the amine terminated dendrimer, and (B) the mixed-termination dendrimer.

Figure 5

Mean force profile for the all-amine dendrimer. The region from 40–51, which corresponds to the attractive hydration forces (due to water ordering), is shown in the close-up in the inset. The mean force is region fits an exponential of the form Ae^−L/λ, where L = r -r_DNA - r_dend is the edge to edge distance (COM-COM reaction coordinate distance r minus the radii of the DNA and dendrimer), A = 345 ±5.78 pN and λ = 0.9 ±0.5 Å.