Lo/Ld Phase Coexistence and Interaction in Model Membranes with IPC Lipids

Abstract

New computational resources, such as Anton, have allowed the study of Lo/Ld phase coexistence in equimolar mixtures of inositol phosphoceramide (IPC), ergosterol (ERG), and phosphatidylinositol (PI) or phosphatidylcholine (PC) lipids. These models are preliminary studies of representative models for the trans-Golgi network and plasma membrane of yeast (Saccharomyces cerevisiae). Our past research on yeast membrane models lacked IPC lipids because at the time ceramide lipids were not fully parameterized for the CHARMM36 lipid force field. Such parameters have been published for sphingolipids (BJ, 107:134-145) and we have extended their use for various ceramides. Phase segregation was shown in IPC/PI/ERG mixtures obtained from separated total lipid extracts of yeast membranes (JBC, 285:30224-30232). Moreover, IPC/PI/ERG had more order than IPC/PC/ERG mixtures, but the reasoning for this is not known. We present the results of two 6μs trajectories of all-atom simulations for each ternary system to probe the formation of lipid domains as well as the increase in order effect of PI vs. PC lipids. Our studies expand on the work of Sodt et al. (JACS, 136:725-732) from simple model systems (DPPC/DOPC/cholesterol) to understanding the effects of head group on the phase behavior and long-chained IPC lipids on potential interleaflet coupling (BJ, 103:2311-2319). We examined lipid diffusion time scales, deuterium order parameters, electron density profiles, lipid head group interaction mechanisms such as hydrogen bonding, and sterol flip-flop timescales.