In silico phase separation in the presence of GM1 in ternary and quaternary lipid bilayers

Abstract

Cell membranes are multi-component mixtures with structural and compositional heterogeneity exhibiting a complex phase behavior. Domains formed in cell membranes often known as "Rafts" are of immense importance. Using coarse grained molecular dynamics simulations, we have studied the spontaneous phase separation of the ternary (POPC [1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine]/cholesterol/GM1) and quaternary (POPC/PSM[palmitoyl sphingomyelin]/cholesterol/GM1) lipid bilayers into liquid ordered (Lo) and liquid disordered (Ld) domains due to self-aggregation of GM1 molecules and co-localization of cholesterol with GM1 in accordance with experiments. It is found that GM1 molecules have the ability to associate strongly with each other which leads to the formation of ordered domains in the lipid mixture and the interactions are through the head group and unsaturated tails present in GM1. Preference of cholesterol for association with GM1 over PSM is observed, the domains consisting of GM1 and cholesterol are formed even in the presence of PSM. PSM also forms small domains with cholesterol that are randomly distributed in the Ld phase. Estimation of dynamic quantities like diffusion coefficient also shows that cholesterol has the highest diffusion rate in the Ld phase which is further attributed to its flip flop ability. It is found that in the presence of PSM, cholesterol can undergo flip flop even in the Lo phase. This is accredited to the interaction of cholesterol with PSM from which it can be concluded that in the presence of PSM, the domains formed by GM1 are less tightly packed and less stable than that in the ternary mixture.

The Ebola virus protein VP40 hexamer enhances the clustering of PI(4,5)P2 lipids in the plasma membrane

“…The fractional interaction matrix, also known as the preferential partitioning of membrane components represents the normalized number of contacts with a specific lipid type and has been used to study lipid phase separation into ordered and disordered domains in various bilayer systems containing peripheral and transmembrane proteins 35 , as well as phase separations 22 and lipid clustering and membrane curvature in various bilayer systems 21 . The fractional interaction matrix is calculated as $$p_{ij}=\frac{C_{ij}/n_j}{{\mathrm{\Sigma }}_k{C}_{ik}/n_k}$$ …”

“…The different types of lipid clustering affect the membrane bending differently and the correlation of such lipid clustering with the membrane curvature has important biological implications 21 . For example, Ipsita et al investigated the clustering of GM1 with or without PSM using CGMD 22 . It was found that in the presence of PSM, the GM1 domains formed loosely bound clusters, whereas in the absence of PSM, they were more strongly bound in the clusters.…”

Ganglioside-Lipid and Ganglioside-Protein Interactions Revealed by Coarse-Grained and Atomistic Molecular Dynamics Simulations

“…Jong et al simulated sorting of proteins to liquid ordered ( L o ) domains induced by gangliosides and lipid anchors. 54 Basu et al 55 and Kociurzynski et al 56 simulated phase separation and transitions of lipid mixtures containing gangliosides.…”

Biophysical insights into the membrane interaction of the core amyloid-forming Aβ40fragment K16–K28 and its role in the pathogenesis of Alzheimer's disease

“…Briefly, eight cholesterol molecules were manually docked to the acyl chains of four GM1 molecules using Hex, 42 assuming the structural influence at the interface of lipid-peptide interaction. 40,45 Additionally, seven POPG molecules were introduced to the system along with KK13, in the center of the box. 44 Herein our molecular setup also implies the equal concentration of cholesterol and GM1 on both layers.…”