Hydrophobic mismatch induces lipid sorting based on tail unsaturation

Biological membranes contain a diverse set of membrane proteins surrounded by many different lipids, and the lateral organization and function of these molecules are closely intertwined. Here, we use coarse-grained molecular dynamics (MD) simulations to explore how hydrophobic mismatch between the length of transmembrane (TM) proteins and the thickness of the surrounding lipid membrane impacts the spatial distribution of the lipids. We constructed idealized cylindrically symmetric proteins, inspired by the "Mattress Model" developed in the 1980's, and simulated these model proteins in different lipid compositions. We found that unsaturated lipids were attracted to short TM proteins that thinned the membrane, while fully saturated lipids were attracted to long TM proteins that induced membrane extension. A simple mechanical description of the membrane deformation energy coupled to a lipid mixing model accurately predicted the enrichment/depletion, which was up to 33% in some cases. Overall, we find that the main driver behind unsaturation-based sorting is the effective lipid length that conforms to match the hydrophobic thickness of the TM protein. Additionally, our simulations highlight that lipid sorting behavior is sensitive to protein tilt and protein surface roughness. By teasing out the fundamental physical principles in these simple models, our results provide a foundational understanding of how proteins and lipids form complex and transient assemblies, which we believe will be important for interpreting lipid-protein interactions for a host of membrane proteins that regulate cellular membranes and cell function.