Mesoscale Computer Modeling of Lipid-DNA Complexes for Gene Therapy

We report on a molecular simulation method, which captures the self-assembly of cationic lipid-DNA (CL-DNA) gene delivery complexes. Computational efficiency required for large length- and time-scale simulations is achieved through a coarse-grained representation of the intramolecular details and via intermolecular potentials, which effectively mimic the hydrophobic effect without an explicit solvent. The broad utility of the model is illustrated by demonstrating excellent agreement with x-ray diffraction experimental data for the dependence of the spacing between DNA chains on the concentration of CLs. At high concentrations, the large electrostatic pressure induces the formation of pores in the membranes through which the DNA molecules may escape the complex. We relate this observation to the origin of recently observed enhanced transfection efficiency of lamellar CL-DNA complexes at high charge densities.

Figure 1

(a) Self-assembly of a 100 lipid bilayer patch. Lipids are modeled as trimers with hydrophilic (black) and hydrophobic (light gray) particles. The membrane in the last figure has been rotated for a better viewing of its structure. (b) Self-assembly of a CL-DNA complex consisting of 240 lipids (of which 90 are charged). Dark gray rods represent DNA segments. (c) Equilibrium configuration of a complex with ${\varphi }_c\sim 0.9$ whose membranes develop pores.

Figure 2

Average DNA spacing $d_{\mathrm{DNA}}$ as a function of the inverse of the fraction of charged lipids $1/{\varphi }_c$. Markers—numerical results (uncertainties are smaller than symbols); solid line—fit to Eq. (1) with $a_{\mathrm{lipid}}=69{\AA }^2$.

Figure 3

(a) Left $y$ axis, solid circles—average area per lipid $a_{\mathrm{lipid}}$ as a function of the fraction of charged lipids ${\varphi }_c$. (b) Right $y$ axis, open squares—effective stretching modulus $K_A^{*}$ of the complex as a function of ${\varphi }_c$.