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It has been a long-standing question how the two leaflets in a lipid bilayer modulate each others' physical properties. In this paper, we discuss how this interaction may take place through interdigitation. We use atomistic molecular dynamics simulations to consider asymmetric lipid membrane models whose compositions are based on the lipidomics data determined for exosomes released by PC-3 prostate cancer cells. The simulations show interdigitation to be exceptionally strong for long-chain sphingomyelin (SM) molecules. In asymmetric membranes the amide-linked chain of SM is observed to extend deep into the opposing membrane leaflet. Interestingly, we find that the conformational order of the amide-linked SM chain increases the deeper it penetrates to the opposing leaflet. Analysis of this finding reveals that the amide-linked SM chain interacts favorably with the lipid chains in the opposite leaflet, and that cholesterol modulates the effect of SM interdigitation by influencing the conformational order of lipid hydrocarbon chains in the opposing (cytosolic) leaflet.

Long-chain sphingomyelin (SM) and glycolipids are not among the most abundant species of lipids, however they can be enriched in specific cells or organelles. For example, lipidomics data determined for exosomes released by PC-3 prostate cancer cells showed that exosomes are particularly enriched in long-chain SM (Biochim. Biophys.Acta, 2013, 1831, 1302–1309). In this study, we use atomistic molecular dynamics simulations to consider asymmetric lipid membrane models whose compositions are based on these data. The simulations show interdigitation of the long-chain SM to the opposite leaflet, which is quite expected, but interestingly we found out that interdigitation was particularly strong in asymmetric bilayers compared to symmetric ones. We observed that the conformational order of the amide-linked SM chain increases the deeper it penetrates to the opposing leaflet. We further showed that cholesterol modulates the effect of SM interdigitation by influencing the conformational order of lipid hydrocarbon chains in the opposing (cytosolic) leaflet.

Glycosylation where glycans are enzymatically attached to proteins is a common post-translational modification among many membrane protein families. The glycans associated with glycosylation serve a variety of structural and functional roles in protein structures, such as recognition and cell-cell adhesion. Determination of glycosylation in membrane protein structures is a complicated matter, though, since due to methodological limitations and the soft nature of glycans, the structure of the crystallized membrane proteins does not include the information arising from glycosylation. Here we use extensive atomistic molecular dynamics simulations together with experimental ligand binding assays and antibodies (1) to show for the N-glycosylated human epidermal growth factor receptor (EGFR) in biomimetic lipid bilayers that N-glycosylation is a crucial determinant of EGFR conformation, and specifically the orientation of the EGFR ectodomain relative to the membrane. It is expected that similar conclusions as to the importance of glycosylation in protein conformational behavior can be drawn for a number of other membrane proteins, too.(1) K. Kaszuba et al., Proc. Natl. Acad. Sci. USA 112, 4334 (2015).

Atomistic molecular dynamics simulations were used to investigate the interactions between the neurotransmitter dopamine and its precursor L-dopa with membrane lipids. The results indicate that these molecules strongly interact with the lipid head groups e.g. via hydrogen bonds. These interactions anchor the dopamine and L-dopa to the membrane interfacial region. The strength of this bonding is dependent on lipids present in membrane. Presence of phosphatidylserine resulted in increased level of bonding strength with a lifetime longer than the timescale of our simulations.The high membrane association of dopamine and L-dopa both, extracellularly, might favour the availability of these compounds for cell membrane uptake processes and, intracellularly, can accentuate the importance of membrane-bound metabolizing enzymes over their soluble counterparts.We can also hypothesize that excessive association of dopamine and its precursor L-dopa with the membranes in the situation, when the concentration of phosphatidylserine is increased, may eventually limit the free use of dopamine as a synaptic transmitter what could possibly be a molecular level mechanism responsible for some of neurodegenerative disorders.View Large Image | View Hi-Res Image | Download PowerPoint Slide