Extracellular and cytosolic leaflets in cellular membranes are distinctly different in lipid composition, yet they contribute together to signaling across the membranes. Here we consider a mechanism based on long-chain gangliosides for coupling the extracellular and cytosolic membrane leaflets together. Based on atomistic molecular dynamics simulations, we find that long-chain GM1 in the extracellular leaflet exhibits a strong tendency to protrude into the opposing bilayer leaflet. This interdigitation modulates the order in the cytosolic monolayer and thereby strengthens the interaction and coupling across a membrane. Coarse-grained simulations probing longer time scales in large membrane systems indicate that GM1 in the extracellular leaflet modulates the phase behavior in the cytosolic monolayer. While short-chain GM1 maintains phase-symmetric bilayers with a strong membrane registration effect, the situation is altered with long-chain GM1. Here, the significant interdigitation induced by long-chain GM1 modulates the behavior in the cytosolic GM1-free leaflet, weakening and slowing down the membrane registration process. The observed physical interaction mechanism provides a possible means to mediate or foster transmembrane communication associated with signal transduction.
The main biological cause of oxysterols is the oxidation of cholesterol. They differ from cholesterol by the presence of additional polar groups that are typically hydroxyl, keto, hydroperoxy, epoxy, or carboxyl moieties. Under typical conditions, oxysterol concentration is maintained at a very low and precisely regulated level, with an excess of cholesterol. Like cholesterol, many oxysterols are hydrophobic and hence confined to cell membranes. However, small chemical differences between the sterols can significantly affect how they interact with other membrane components, and this in turn can have a substantial effect on membrane properties. In this spirit, this review describes the biological importance and the roles of oxysterols in the human body. We focus primarily on the effect of oxysterols on lipid membranes, but we also consider other issues such as enzymatic and nonenzymatic synthesis processes of oxysterols as well as pathological conditions induced by oxysterols.
- MeSH
- cholesterol metabolismus MeSH
- lidé MeSH
- lipidové dvojvrstvy metabolismus MeSH
- nemoc MeSH
- oxidace-redukce MeSH
- oxysteroly metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Cholesteryl hemisuccinate (CHS) is one of the cholesterol-mimicking detergents not observed in nature. It is, however, widely used in protein crystallography, in biochemical studies of proteins, and in pharmacology. Here, we performed an extensive experimental and theoretical study on the behavior of CHS in lipid membranes rich in unsaturated phospholipids. We found that the deprotonated form of CHS (that is the predominant form under physiological conditions) does not mimic cholesterol very well. The protonated form of CHS does better in this regard, but also its ability to mimic the physical effects of cholesterol on lipid membranes is limited. Overall, although ordering and condensing effects characteristic to cholesterol are present in systems containing any form of CHS, their strength is appreciably weaker compared to cholesterol. Based on the considerable amount of experimental and atomistic simulation data, we conclude that these differences originate from the fact that the ester group of CHS does not anchor it in an optimal position at the water-membrane interface. The implications of these findings for considerations of protein-cholesterol interactions are briefly discussed.
- MeSH
- 2-naftylamin analogy a deriváty chemie MeSH
- cholesterol chemie MeSH
- dihydropyridiny chemie MeSH
- estery cholesterolu chemie MeSH
- fosfatidylcholiny chemie MeSH
- laurany chemie MeSH
- lipidové dvojvrstvy chemie MeSH
- liposomy chemie MeSH
- protony * MeSH
- simulace molekulární dynamiky MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The behavior of oxysterols in phospholipid membranes and their effects on membrane properties were investigated by means of dynamic light scattering, fluorescence spectroscopy, NMR, and extensive atomistic simulations. Two families of oxysterols were scrutinized-tail-oxidized sterols, which are mostly produced by enzymatic processes, and ring-oxidized sterols, formed mostly via reactions with free radicals. The former family of sterols was found to behave similar to cholesterol in terms of molecular orientation, roughly parallel to the bilayer normal, leading to increasing membrane stiffness and suppression of its membrane permeability. In contrast, ring-oxidized sterols behave quantitatively differently from cholesterol. They acquire tilted orientations and therefore disrupt the bilayer structure with potential implications for signaling and other biochemical processes in the membranes.
We study how lipid probes based on pyrene-labeling could be designed to minimize perturbations in lipid bilayers, and how the same design principles could be exploited to develop probes which gauge lipid dynamics primarily within a single lipid monolayer or between them. To this end, we use atomistic molecular dynamics simulations to consider membranes where pyrene moieties are attached to lipid acyl chains in varying positions. We find that in a DOPC bilayer the conformational ordering of lipids around di-pyrenyl-PC probes is altered to a largely similar extent regardless of where the pyrene moiety is attached to the hydrocarbon chain. This is in contrast to saturated membranes, where pyrene-induced perturbations have been observed to be more prominent. Meanwhile, the formation of pyrene dimers depends on the linkage point between pyrene and its host lipid. Membrane-spanning dimers between lipids in different membrane leaflets are observed only if the pyrene moiety is attached to the latter half of the acyl chain. A seemingly minor change to link pyrene to an acyl chain that is two carbons shorter leads to a situation where membrane-spanning dimers are no longer observed. Further, simulations suggest that formation of dimers is a slow process, where the rate is limited by both lateral diffusion and the dimerization process once the two probes are neighbors to one another. Typical lifetimes of pyrene dimers turn out be of the order of nanoseconds. The results are expected to pave the way for designing ways to consider experimentally topics such as intraleaflet lateral diffusion, motion of lipids within and between membrane domains, and membrane domain registration across bilayers.
- MeSH
- buněčná membrána chemie účinky léků MeSH
- časové faktory MeSH
- dimerizace * MeSH
- fluorescenční barviva chemie farmakologie MeSH
- lipidové dvojvrstvy chemie MeSH
- membránové lipidy chemie MeSH
- pyreny chemie farmakologie MeSH
- uhlovodíky chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The lateral pressure profile of lipid bilayers has gained a lot of attention, since changes in the pressure profile have been suggested to shift the membrane protein conformational equilibrium. This relation has been mostly studied with theoretical methods, especially with molecular dynamics simulations, since established methods to measure the lateral pressure profile experimentally have not been available. The only experiments that have attempted to gauge the lateral pressure profile have been done by using di-pyrenyl-phosphatidylcholine (di-pyr-PC) probes. In these experiments, the excimer/monomer fluorescence ratio has been assumed to represent the lateral pressure in the location of the pyrene moieties. Here, we consider the validity of this assumption through atomistic molecular dynamics simulations in a DOPC (dioleoylphosphatidylcholine) membrane, which hosts di-pyr-PC probes with different acyl chain lengths. Based on the simulations, we calculate the pyrene dimerization rate and the lateral pressure at the location of the pyrenes. The dimerization rates are compared with the results of di-pyr-PC probes simulated in vacuum. The comparison indicates that the lateral pressure is not the dominant determinant of the excimer/monomer fluorescence ratio. Thus, the results do not support the usage of di-pyr-PC molecules to measure the shape of the lateral pressure profile. We yet discuss how the probes could potentially be exploited to gain qualitative insight of the changes in pressure profile when lipid composition is altered.
