On the other hand, ECC makes the β-carbon order parameter less sensitive, and α-carbon slightly more sensitive, to both etidocaine and TPP. This brings the responses to the number of bound molecules in Fig. closer to experiments, although the decrease in β-carbon upon addition of etidocaine is now slightly underestimated. In conclusion, ECC potentially improves the interactions of etidocaine and TPP with the POPC headgroup. However, it introduces too strong binding affinity, emphasizing the need for further optimization of force field parameters to accurately capture the binding details of TPP, etidocaine and other charged small molecules to lipid membranes.