Coarse-grained simulations of branched bilayer membranes: effects of cholesterol-dependent phase separation on curvature-driven lipid sorting  

作　　者：Manami Nishizawa Kazuhisa Nishizawa 

机构地区：[1]Department of Laboratory Medicine, Teikyo University School of Medical Technology, Tokyo, Japan

出　　处：《Journal of Biophysical Chemistry》2011年第3期268-284,共17页生物物理化学（英文）

摘　　要：Our recent coarse-grained (CG) molecular dynamics (MD) simulations of membranes with a hemifused-ribbon (λ-shaped) geometry showed curvature-driven demixing leading to enrich ment in dioleoyl-phosphatidylethanolamine (DOPE) in a negatively-curved region (at C = –0.8 nm–1) of a DOPE/dipalmitoyl-phosphati-dylcholine (DPPC) membrane. Here we extend the analysis with respect to lipid composition and simulation time. Simulations of 12 – 20 μs effective time show that, compared with DOPE of the DOPE/DPPC system, a DPPC/dilinoleyl-PC [di(18:2)PC] membrane showed a similar degree of enrichment of di(18:2)PC in the curved region with C=–0.8 nm–1. For the latter mixture, even weak negative curvatures (C=–0.5 – 0.6 nm–1) caused significant degrees of di(18:2)PC enrichment. In agreement with recent studies of a planar bilayer, a ternary DPPC/ di(18:2)PC/cholesterol 0.42:0.28:0.3 mixture phase-separated into nanoscale raft-like liquid-ordered (Lo) and non-raft liquid-disordered (Ld) phases on a sub-microsecond time scale. The Lo domains were preferentially localized at planar portions, whereas the Ld domains were positioned mainly in curved regions of the membrane. Unlike binary dioleoylphosphatidylcho-line (DOPC)/cholesterol and DPPC/cholesterol mixtures, which showed only a slight enrich ment of cholesterol in the curved region, the ternary mixtures showed considerable migra tion of cholesterol and DPPC from the curved to the planar region. A pronounced degree of lipid segregation due to the preferential distribution of the Ld and Lo domains in the curved and planar regions, respectively, was observed even when the curvature of the fused monolayers (originally ‘cis’ leaflets) was weakened (C= –0.5 nm-1). Overall, the results are consistent with theoretical predictions based on spontaneous curvature of the constituent lipids and the difference in rigidity between the Ld and Lo domains, whereas lipid-lipid interactions, such as PE-PE or DPPC-cholesterol, as well as propensity for interleaflet colocalizOur recent coarse-grained (CG) molecular dynamics (MD) simulations of membranes with a hemifused-ribbon (λ-shaped) geometry showed curvature-driven demixing leading to enrich ment in dioleoyl-phosphatidylethanolamine (DOPE) in a negatively-curved region (at C = –0.8 nm–1) of a DOPE/dipalmitoyl-phosphati-dylcholine (DPPC) membrane. Here we extend the analysis with respect to lipid composition and simulation time. Simulations of 12 – 20 μs effective time show that, compared with DOPE of the DOPE/DPPC system, a DPPC/dilinoleyl-PC [di(18:2)PC] membrane showed a similar degree of enrichment of di(18:2)PC in the curved region with C=–0.8 nm–1. For the latter mixture, even weak negative curvatures (C=–0.5 – 0.6 nm–1) caused significant degrees of di(18:2)PC enrichment. In agreement with recent studies of a planar bilayer, a ternary DPPC/ di(18:2)PC/cholesterol 0.42:0.28:0.3 mixture phase-separated into nanoscale raft-like liquid-ordered (Lo) and non-raft liquid-disordered (Ld) phases on a sub-microsecond time scale. The Lo domains were preferentially localized at planar portions, whereas the Ld domains were positioned mainly in curved regions of the membrane. Unlike binary dioleoylphosphatidylcho-line (DOPC)/cholesterol and DPPC/cholesterol mixtures, which showed only a slight enrich ment of cholesterol in the curved region, the ternary mixtures showed considerable migra tion of cholesterol and DPPC from the curved to the planar region. A pronounced degree of lipid segregation due to the preferential distribution of the Ld and Lo domains in the curved and planar regions, respectively, was observed even when the curvature of the fused monolayers (originally ‘cis’ leaflets) was weakened (C= –0.5 nm-1). Overall, the results are consistent with theoretical predictions based on spontaneous curvature of the constituent lipids and the difference in rigidity between the Ld and Lo domains, whereas lipid-lipid interactions, such as PE-PE or DPPC-cholesterol, as well as propensity for interleaflet colocaliz

关 键 词：LIPID Raft Stalk Formation Membrane Rigidity LIPID Clustering LIPID SORTING LIPID Mixing HEMIFUSION Cholesterol-Rich MICRODOMAIN 

分 类 号：R73[医药卫生—肿瘤]