Structural and energetic transformations in the plasma membrane of a cancerous cell are investigated together with related consequences for the insertion of small cationic compounds. Molecular dynamics simulations are performed with an empirical force field on two membrane models that represent the membrane of a cancerous cell (M-
Cancer) and of a healthy cell (M-Eukar), respectively. An eight-fold increase of negatively charged
phosphatidylserine in the external membrane layer as well as a reduction of
cholesterol concentration by half is taken into account to describe the membrane transformation. Three additional reference membranes are prepared and consist of pure
phosphatidylcholine (M-PC), where 20% is replaced with
phosphatidylserine (M-PC0.8S0.2), and where 34% is replaced with
cholesterol (M-PC0.66Ch0.34), respectively. Moreover, the free energy released by inserting octadecylmethylimidazolium (OMIM(+)), a
cation found in a class of common
ionic liquids, into M-Eukar, M-
Cancer as well as into the three reference model membranes is derived by applying thermodynamic integration. We find that the presence of
serine improves the solvation of the membrane through favorable electrostatic interactions with solvated
sodium ions, where a significant number of
sodium ions are capable of penetrating the upper polar layer of the membrane. However, the insertion free energy of OMIM(+) does not seem to be influenced by
serine in the membrane. Furthermore, a significant
serine induced structural reorganization of the membrane is not observed. In contrast, a reduction of
cholesterol in the membrane models leads to smaller
lipid surface densities, thinner membranes as well as less ordered and less stretched
lipids as expected. We also observe that
cholesterol reduction leads to a rougher membrane surface and an increased
solvent accessibility of the hydrophobic membrane core. Membrane insertion of OMIM(+) becomes significantly more favorable in the absence of
cholesterol, with an increased insertion free energy release of 7.1 kJ mol(-1) in M-
Cancer compared to M-Eukar. Overall, the results suggest only a minor influence of
serine on membrane organization but do not rule out an influence on
cation insertion through a stronger
cation adsorption to the membrane surface. In contrast,
cholesterol seems to impede OMIM(+) insertion by increasing the density of polar
lipids on the membrane surface and by flattening the membrane surface. These observations are shedding some light on the previously observed selective disruption of cancerous cells induced by cationic compounds such as found in
ionic liquids.