Membrane heterogeneity alters our interpretation of effective energy barriers to transport

Major efforts in recent years have been directed towards understanding molecular transport in polymeric membranes. Transition-state theory is an increasingly common approach to explore mechanisms of transmembrane permeation with molecular details, but most applications treat all free energy barriers to transport as equal. This assumption neglects the inherent structural and chemical heterogeneity in polymeric membranes. In this work, we expand the transition-state theory framework to include distributions of membrane free energy barriers. We show that the highest free energy barriers along the most permeable paths, rather than typical paths, provide the largest contributions to the experimentally-observed effective free energy barrier. We show that even moderate, random heterogeneity in molecular barriers will significantly impact how we interpret the mechanisms of transport through membranes. Naive interpretations of experimentally measured barriers can lead to incorrect assumptions about the underlying mechanisms governing transport and miss the mechanisms most relevant to the overall permeability.