Molecular Organization of a Raft-like Domain in a Polyunsaturated Phospholipid Bilayer: A Supervised Machine Learning Analysis of Molecular Dynamics Simulations
Samuel W. Canner, Scott E. Feller, Stephen R. Wassall
Abstract
Numerous health benefits are associated with omega-3 polyunsaturated fatty acids (n-3 PUFA) consumed in fish oils. An understanding of the mechanism remains elusive. The plasma membrane as a site of action is the focus in this study. With large-scale all-atom MD simulations run on a model membrane (1050 lipid molecules), we observed the evolution over time (6 μs) of a circular (raft-like) domain composed of N-palmitoylsphingomyelin (PSM) and cholesterol embedded into a surrounding (non-raft) patch composed of polyunsaturated 1-palmitoyl-2-docosahexaenoylphosphatylcholine (PDPC) (1:1:1 mol). A supervised machine learning algorithm was developed to characterize the migration of each lipid based on molecular conformation and the local environment. PDPC molecules were seen to infiltrate the ordered raft-like domain in a small amount, while a small concentration of PSM and cholesterol molecules was seen to migrate into the disordered non-raft region. Enclosing the raft-like domain, a narrow (∼2 nm in width) interfacial zone composed of PDPC, PSM, and cholesterol that buffers the substantial difference in order (ΔSCD ≈ 0.12) between raft-like and non-raft environments was seen to form. Our results suggest that n-3 PUFA regulate the architecture of lipid rafts enriched in sphingolipids and cholesterol with a minimal effect on order within their interior in membranes.