For simulations with the standard force fields, CHARMM36 parameters 36 from CHARMM-GUI were used for lipids. Parameters for etidocaine were generated with two standard approaches: SwissParam 40 from , denoted here as CHARMM36-SwissParam, and Cgenff (CHARMM general force field) from , denoted here as CHARMM36-ParamChem. For TPP, the standard approaches cannot be used since there are no parameters for the phosphonium atom. Therefore, we used CHARMM atom types together with the charges calculated using Gaussian using Density Functional Theory (DFT) B3LYP functional and CHELPG scheme (CHarges from ELectrostatic Potentials using a Grid based method), denoted here as CHARMM36-QMcharges. Partial charges from our Gaussian calculation slightly deviated from the ones reported in literature, see Fig. in the supporting information (SI). Binding affinities to membranes were tested with both charges, but the results were similar, and only the results with our parameters from Gaussian (CHARMM36-QMcharges) are shown. In another approach, denoted here as CHARMM36-ProteinFF, charges for TPP were obtained from the phenyl ring of phenylalanine in the CHARMM36 protein force field. All the systems were run with the TIP3P CHARMM36 water model. For simulations with ECC, we used our recently parametrized model compatible with CHARMM36 for POPC (PN-model in Ref. 47). Following the simplest ECC approach, all partial charges in CHARMM36-ParamChem parameters of etidocaine (table S1 in the SI) and CHARMM36-QMcharges of TPP (Fig. in the SI) were scaled by 0.75. Partial charges used in all etidocaine and TPP simulations are listed in Fig. and table S1 in the SI.