How a few help all: Cooperative crossing of lipid membranes by COSAN anions

Lipid membranes are notorious for their ability to maintain ionic concentration gradients, acting as efficient barriers to ions. However, the validity of this statement for nano-ions (ions of nanometric size which are in fact small charged molecules) is not obvious. Experimental results show that the presence of a concentration gradient of certain nano- ions (most notably cobaltabisdicarbollide ([o-COSAN] − an- ions), induce a current across intact artificial phospholipid bilayers. The mechanism underlying this observed translo- cation of nano-anions across membranes is unknown. Here we show, using molecular dynamics simulations, that the permeation of [o-COSAN] − anions across a lipid bilayer pro- ceeds in a cooperative manner. Single nano-ions can enter the bilayer but they cannot cross it due to a free energy barrier of about 8k B T . The interaction between these nano- ions inside a leaflet induces a flip-flop translocation mech- anism with the formation of transient, elongated structure inside the membrane. This cooperative flip-flop allows an efficient distribution of [o-COSAN] − anions in both bilay- ers of the membrane. These results suggest the existence of a new mechanism for permeation of nano-ions across lipid membranes, relevant for those that have the appropriate self-assembly character.