Lidocaine accelerates electroporation of lipid bilayers: A molecular dynamics study.

Abstract

Lidocaine, a local anaesthetic administered during procedures such as electrochemotherapy and gene electrotransfer, has been reported to sensitise cells to electroporation at millimolar concentrations. However, whether and how it acts on the lipid membrane itself to influence pore formation is not known. Using atomistic molecular dynamics simulations, we followed electroporation in three bilayers of increasing complexity - POPC, asymmetric POPC+POPS, and a fifteen-component complex bilayer - each containing uncharged or charged lidocaine at two concentrations. Under a constant transmembrane voltage, lidocaine shortened the time to poration in nearly every condition. The effect increased with concentration, was more consistent for the uncharged form, and was greatest in the two simpler bilayers, where the median time to poration at 50 mM decreased from about 20 ns to a few nanoseconds, and smallest in the complex, most cell-like membrane. Pores formed preferentially near membrane-bound lidocaine, suggesting that it favours pore nucleation locally. Lidocaine also acted globally, by increasing the area per lipid and thinning the bilayer, which lowers the barrier to pore nucleation throughout the membrane. These results provide a molecular basis for how lidocaine modifies the membrane's response to an electric field.

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