Exploring the Limits of Passive Macromolecular Translocation through Phospholipid Membranes

Transportation of active macromolecules through cell membranes is an essential biological process. However, for hydrophilic macromolecules, the hydrophobic interior of lipid bilayers suppresses the passive translocation, and there are only few cases reported. We use alternating amphiphilic polymers (AAPs) in which the sizes of the hydrophilic and hydrophobic units can be varied over a broad range, keeping the polymers water-soluble. For small units, the macromolecules show a homopolymer-like character. Pulse field gradient NMR and neutron reflectivity measurements show that the chains have a high solubility in the membrane hydrophobic interior that allows the chains to passively translocate. Increasing the length of the hydrophilic units leads to more polar AAPs with low membrane solubility and a reduced translocation speed. If hydrophilic and hydrophobic moieties are increased in size, the AAPs have a strong amphiphilic character and adsorb to lipid membranes only with their hydrophobic units, have a high membrane concentration, and have an overall fast translocation kinetics.