Using molecular dynamics simulations, we have explored the effect of asymmetric lipids specifically those that contain one polyunsaturated (PUFA) and one saturated fatty acid chain on phase separation in heterogeneous membranes. These lipids are prevalent in neuronal membranes, particularly in synaptic membranes, where the Parkinson's Disease protein a-Synuclein (alpha S) is found. We have therefore explored the relationship between asymmetric, PUFA-containing lipids, and aS. The simulations show that asymmetric lipids partition to the liquid disordered (Ld) phase of canonical raft mixtures because of the highly disordered PUFA chain. In the case of a membrane built to mimic the lipid composition of a synaptic vesicle, the PUFA-containing asymmetric lipids completely disrupt phase separation. Because aS is positively charged, we show that it partitions with negatively charged lipids, regardless of the saturation state of the chains. Additionally, aS preferentially associates with the polyunsaturated fatty add tails of both charged and neutral lipids. This is a consequence of those chains' ability to accommodate the void beneath the amphipathic helix. This article is part of a Special Issue entitled: Lipid order/ lipid defects and lipid-control of protein activity edited by Dirk Schneider. (C)2016 Published by Elsevier B.V.