Computational and analytical modeling of cationic lipid-DNA complexes

¹ Ben Gurion University
² University of California, Davis

^* To whom correspondence should be addressed. E-mail: ngjensen{at}ucdavis.edu.

Submitted on September 7, 2006
Revised on November 9, 2006
Accepted on 11 December 2006

	Abstract

We present a theoretical study of the physical properties of cationic lipid-DNA (CL-DNA) complexes - a promising synthetically based nonviral carrier of DNA for gene therapy. The study is based on a coarse-grained molecular model, which is used in Monte Carlo (MC) simulations of mesoscopically large systems over time scales long enough to address experimental reality. In the present work we focus on the statistical-mechanical behavior of lamellar complexes, which in MC simulations self-assemble spontaneously from a disordered random initial state. We measure the DNA-interaxial spacing, d_DNA, and the local cationic area charge density, _M, for a wide range of values of the parameter _c representing the fraction of cationic lipids. For weakly charged complexes (low values of _c), we find that d_DNA has a linear dependence on _c^-1, which is in excellent agreement with x-ray diffraction experimental data. We also observe, in qualitative agreement with previous Poisson-Boltzmann calculations of the system, large fluctuations in the local area charge density with a pronounced minimum of _M halfway between adjacent DNA molecules. For highly-charged complexes (large _c), we find moderate charge density fluctuations and observe deviations from linear dependence of d_DNA on _c^-1. This last result, together with other findings such as the decrease in the effective stretching modulus of the complex and the increased rate at which pores are formed in the complex membranes, are indicative of the gradual loss of mechanical stability of the complex which occurs when _c becomes large. We suggest that this may be the origin of the recently observed enhanced transfection efficiency of lamellar CL-DNA complexes at high charge densities, because the completion of the transfection process requires the disassembly of the complex and the release of the DNA into the cytoplasm. Some of the structural properties of the system are also predicted by a continuum free energy minimization. The analysis, which semi-quantitatively agrees with the computational results, shows that that mesoscale physical behavior of CL-DNA complexes is governed by an interplay between electrostatic, elastic, and mixing free energies.

Key Words: Coarse grained modeling, Molecular simulation, biomolecular assemblies, electrostatic interactions, gene delivery

This article has been cited by other articles:

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