Modifying membrane permeability with ionic liquids

Abstract

Room temperature ionic liquids (ILs) have been proven to have a range of biological applications, from influencing protein folding and structural stability, to affecting enzyme activity, to modifying the permeability profile of lipid bilayers. In this work we use all-atom molecular dynamics simulations to study the effects of the ionic liquid choline geranate (CAGE) on lipid bilayers composed of POPE and POPC lipid types. CAGE was chosen based on previous experimental work that demonstrated this IL is effective at eradicating bacterial biofilms and at increasing the permeability of the biofilms to several antibiotics and other small molecules (Fig. 1).1 In order to measure the effect of ILs on the permeability of lipid bilayers, we are using an enhanced sampling technique known as adaptively biased molecular dynamics (ABMD)2 to measure the free energy associated with the motion of the choline, geranate, and geranic acid components of the IL through pure POPE and POPC membranes. In the ABMD method, an energetic bias is applied to the system that accelerates the exploration of the ionic liquid molecules between the aqueous and lipid phases of the system, similar to the principles of the metadynamics method3. The free energies calculated from ABMD will also be compared to the results of umbrella sampling (US) simulations. By comparing the ABMD and US methods we will be able to demonstrate whether the ABMD approach is well-suited for studying membrane permeability to ILs. The next phase of the project seeks to contrast the permeability of several pharmaceutical compounds in the same membranes with and without ILs. From these simulations we will be able to determine how the presence of ILs impact the free energy profile of small drugs across the membrane.