Molecular Mechanism of Polycation-Induced Pore Formation in Biomembranes

Polycations
are an attractive class of macromolecules with promising
applications as drug/gene carriers and biocides. The chemical structure
and concentration of a polycation determine its interaction with cellular
membranes and, hence, are crucial parameters for designing efficient
nontoxic polycations. However, the interaction of polycations with
biomembranes at the molecular level and the corresponding free-energy
landscape is not well understood. In this work, we investigate the
molecular mechanism of interaction between a strong polycation substituted
with alkyl moieties and zwitterionic membranes via long-time-scale
all-atom molecular dynamics simulations and free-energy calculations
combined with Langmuir monolayer, atomic force microscopy, and calcein-release
experimental measurements. We found that the membrane activity of
the polycation and its ability to induce pores in the membranes can
be attributed to the polycation-induced changes in the bilayer organization,
such as reduced membrane thickness, increased disorder of the acyl
chains, reduced packing, and electrostatic field gradients between
membrane leaflets. These changes facilitate the penetration of water
into the membrane and the formation of aqueous defects/pores. The
calculated free-energy profiles indicate that the polycation lowers
the nucleation barrier for pore opening and the free energy for pore
formation in a concentration-dependent manner. Above the critical
coverage of the membrane, the polycation nucleates spontaneous pores
in zwitterionic membranes. Our work demonstrates the potential of
combining enhanced sampling methods in MD simulations with experiments
for a quantitative description of various events in the polycation-membrane
interaction cycle, such as strong adsorption on the membrane due to
hydrophobic and electrostatic interactions, and pore formation.