For small molecules with charges surrounded by hydrophobic moieties, such as etidocaine and TPP, the hydrophobic effect is the most likely driving force for their membrane binding. In the case of calcium, the inclusion of ECC reduces the electrostatic attraction with phosphate oxygen, which is the most likely reason for the reduced binding affinity. Indeed, the reduction in interactions with phosphate oxygen due to ECC is observed for calcium in table 1, but not for etidocaine or TPP. On the other hand, the scaling of total charge by ECC makes etidocaine and TPP less soluble in water, thereby increasing their binding affinity to membranes. In conclusion, the binding behaviour of mono atomic ions, such as calcium, to membranes differs from small molecules, such as etidocaine and TPP, due to their different binding mechanisms. Comparison of sodium, calcium, etidocaine and TPP binding to membranes