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The present review is an attempt to conceptualize a contemporary understanding about the roles that cardiolipin, a mitochondrial specific conical phospholipid, and non-bilayer structures, predominantly found in the inner mitochondrial membrane (IMM), play in mitochondrial bioenergetics. This review outlines the link between changes in mitochondrial cardiolipin concentration and changes in mitochondrial bioenergetics, including changes in the IMM curvature and surface area, cristae density and architecture, efficiency of electron transport chain (ETC), interaction of ETC proteins, oligomerization of respiratory complexes, and mitochondrial ATP production. A relationship between cardiolipin decline in IMM and mitochondrial dysfunction leading to various diseases, including cardiovascular diseases, is thoroughly presented. Particular attention is paid to the targeting of cardiolipin by Szeto-Schiller tetrapeptides, which leads to rejuvenation of important mitochondrial activities in dysfunctional and aging mitochondria. The role of cardiolipin in triggering non-bilayer structures and the functional roles of non-bilayer structures in energy-converting membranes are reviewed. The latest studies on non-bilayer structures induced by cobra venom peptides are examined in model and mitochondrial membranes, including studies on how non-bilayer structures modulate mitochondrial activities. A mechanism by which non-bilayer compartments are formed in the apex of cristae and by which non-bilayer compartments facilitate ATP synthase dimerization and ATP production is also presented.
- Klíčová slova
- ATP synthase, cardiolipin, cardiovascular disease, electron-transport chain, inner mitochondrial membrane, non-bilayer structures,
- MeSH
- energetický metabolismus * MeSH
- kardiolipiny chemie metabolismus MeSH
- kardiovaskulární nemoci metabolismus MeSH
- lidé MeSH
- lipidové dvojvrstvy metabolismus MeSH
- mitochondriální membrány metabolismus MeSH
- mitochondrie metabolismus patologie ultrastruktura MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- kardiolipiny MeSH
- lipidové dvojvrstvy MeSH
Up to now the lipid bilayers were rarely considered as targets in cancer therapy despite pronounced differences in lipid composition between plasma membranes of benign and malignant cells. In this study we demonstrate that the lipid bilayer of the plasma membrane is druggable and suitable for facilitating selective delivery of amphiphilic gemcitabine-squalene nanomedicines to cancer cells. Data from radioactive assays, fluorescent membrane probes and molecular dynamics simulations provide evidence of selective accumulation of gemcitabine-squalene in the plasma membranes with disrupted lipid asymmetry and its subsequent preferential uptake by malignant cells. This causes pronounced cytotoxicity on cancer cells in comparison to their benign counterparts originating from the same tissue.
- Klíčová slova
- Cancer targeting, Gemcitabine-squalene, Lipid composition, Nanomedicine, Plasma membrane, Selective delivery,
- MeSH
- buněčná membrána metabolismus MeSH
- gemcitabin MeSH
- lipidové dvojvrstvy metabolismus MeSH
- nádory * metabolismus MeSH
- prekurzory léčiv * MeSH
- skvalen metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- gemcitabin MeSH
- lipidové dvojvrstvy MeSH
- prekurzory léčiv * MeSH
- skvalen MeSH
The 'standard' fluid-mosaic membrane model can provide a framework for the operation of the photosynthetic and respiratory electron transport systems, the generation of the proton motive force (pmf) and its utilization for ATP synthesis according to the chemiosmotic theory. However, this model, with the bilayer organization of all lipid molecules, assigns no function to non-bilayer lipids - while in recent years it became clear that the two fundamental energy transducing membranes of the biosphere, chloroplast thylakoid membranes (TMs) and inner mitochondrial membranes (IMMs), contain large amounts of non-bilayer (non-lamellar) lipid phases. In this review, we summarize our understanding on the role of non-lamellar phases in TMs and IMMs: (i) We propose that for these membrane vesicles the dynamic exchange model (DEM) provides a more suitable framework than the 'standard' model; DEM complements the 'standard' model by assuming the co-existence of bilayer and non-bilayer phases and their interactions, which contribute to the structural dynamics of the membrane systems and safe-guard the membranes' high protein:lipid ratios. (ii) Non-bilayer phases play pivotal roles in membrane fusion and intermembrane lipid exchanges - essential processes in the self-assembly of these highly folded intricate membranes. (iii) The photoprotective, lipocalin-like lumenal enzyme, violaxanthin de-epoxidase, in its active state requires the presence of non-bilayer lipid phase. (iv) Cardiotoxins, water-soluble polypeptides, induce non-bilayer phases in mitochondria. (v) ATP synthesis, in mammalian heart IMMs, is positively correlated with the amount of non-bilayer packed lipids with restricted mobility. (vi) The hypothesized sub-compartments, due to non-lamellar phases, are proposed to enhance the utilization of pmf and might contribute to the recently documented functional independence of individual cristae within the same mitochondrion. Further research is needed to identify and characterize the structural entities associated with the observed non-bilayer phases; and albeit fundamental questions remain to be elucidated, non-lamellar lipid phases should be considered on a par with the bilayer phase, with which they co-exist in functional TMs and IMMs.
- Klíčová slova
- ATP synthesis, Dynamic exchange between lipid phases, Fusion and fission of membranes, Inner mitochondrial membranes, Non-bilayer lipids, Thylakoid membranes,
- MeSH
- adenosintrifosfát MeSH
- lipidové dvojvrstvy MeSH
- lipidy chemie MeSH
- mitochondriální membrány * MeSH
- savci MeSH
- tylakoidy * chemie MeSH
- voda MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- adenosintrifosfát MeSH
- lipidové dvojvrstvy MeSH
- lipidy MeSH
- voda MeSH
Earlier experiments, using 31 P-NMR and time-resolved merocyanine fluorescence spectroscopy, have shown that isolated intact, fully functional plant thylakoid membranes, in addition to the bilayer phase, contain three non-bilayer (or non-lamellar) lipid phases. It has also been shown that the lipid polymorphism of thylakoid membranes can be characterized by remarkable plasticity, i.e. by significant variations in 31 P-NMR signatures. However, changes in the lipid-phase behaviour of thylakoids could not be assigned to changes in the overall membrane organization and the photosynthetic activity, as tested by circular dichroism and 77 K fluorescence emission spectroscopy and the magnitude of the variable fluorescence of photosystem II, which all showed only marginal variations. In this work, we investigated in more detail the temporal stability of the different lipid phases by recording 31 P-NMR spectra on isolated thylakoid membranes that were suspended in sorbitol- or NaCl-based media. We observed, at 5°C during 8 h in the dark, substantial gradual enhancement of the isotropic lipid phases and diminishment of the bilayer phase in the sorbitol-based medium. These changes compared well with the gradually increasing membrane permeability, as testified by the gradual acceleration of the decay of flash-induced electrochromic absorption changes and characteristic changes in the kinetics of fast chlorophyll a-fluorescence transients; all variations were much less pronounced in the NaCl-based medium. These observations suggest that non-bilayer lipids and non-lamellar lipid phases play significant roles in the structural dynamics and functional plasticity of thylakoid membranes.
- MeSH
- fotosystém II - proteinový komplex metabolismus MeSH
- intracelulární membrány metabolismus MeSH
- kinetika MeSH
- lipidové dvojvrstvy metabolismus MeSH
- magnetická rezonanční spektroskopie MeSH
- tylakoidy metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- fotosystém II - proteinový komplex MeSH
- lipidové dvojvrstvy MeSH
Molecular dynamics (MD) simulations have become a highly important technique to consider lipid membrane systems, and quite often they provide considerable added value to laboratory experiments. Rapid development of both software and hardware has enabled the increase of time and size scales reachable by MD simulations to match those attainable by several accurate experimental techniques. However, until recently, the quality and maturity of software tools available for building membrane models for simulations as well as analyzing the results of these simulations have seriously lagged behind. Here, we discuss the recent developments of such tools from the end-users' point of view. In particular, we review the software that can be employed to build lipid bilayers and other related structures with or without embedded membrane proteins to be employed in MD simulations. Additionally, we provide a brief critical insight into force fields and MD packages commonly used for membrane and membrane protein simulations. Finally, we list analysis tools that can be used to study the properties of membrane and membrane protein systems. In all these points we comment on the respective compatibility of the covered tools. We also share our opinion on the current state of the available software. We briefly discuss the most commonly employed tools and platforms on which new software can be built. We conclude the review by providing a few ideas and guidelines on how the development of tools can be further boosted to catch up with the rapid pace at which the field of membrane simulation progresses. This includes improving the compatibility between software tools and promoting the openness of the codes on which these applications rely. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Róg.
- Klíčová slova
- Lipid bilayer, Membrane building, Molecular dynamics, Protein insertion, Tools and software,
- MeSH
- databáze jako téma MeSH
- lipidové dvojvrstvy chemie MeSH
- liposomy MeSH
- membránové proteiny chemie MeSH
- micely MeSH
- simulace molekulární dynamiky * MeSH
- software MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- lipidové dvojvrstvy MeSH
- liposomy MeSH
- membránové proteiny MeSH
- micely MeSH
Over the past decade, molecular dynamics (MD) simulations have become particularly powerful to rationalize drug insertion and partitioning in lipid bilayers. MD simulations efficiently support experimental evidences, with a comprehensive understanding of molecular interactions driving insertion and crossing. Prediction of drug partitioning is discussed with respect to drug families (anesthetics; β-blockers; non-steroidal anti-inflammatory drugs; antioxidants; antiviral drugs; antimicrobial peptides). To accurately evaluate passive permeation coefficients turned out to be a complex theoretical challenge; however the recent methodological developments based on biased MD simulations are particularly promising. Particular attention is paid to membrane composition (e.g., presence of cholesterol), which influences drug partitioning and permeation. Recent studies concerning in silico models of membrane proteins involved in drug transport (influx and efflux) are also reported here. These studies have allowed gaining insight in drug efflux by, e.g., ABC transporters at an atomic resolution, explicitly accounting for the mandatory forces induced by the surrounded lipid bilayer. Large-scale conformational changes were thoroughly analyzed.
- Klíčová slova
- Active transport, Drug-membrane interactions, In silico models, Lipid bilayer membranes, Molecular dynamics, Passive permeation,
- MeSH
- biologický transport MeSH
- buněčná membrána metabolismus MeSH
- cytoplazma metabolismus MeSH
- léčivé přípravky metabolismus MeSH
- léková rezistence MeSH
- lidé MeSH
- lipidové dvojvrstvy metabolismus MeSH
- membránové proteiny metabolismus MeSH
- počítačová simulace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- léčivé přípravky MeSH
- lipidové dvojvrstvy MeSH
- membránové proteiny MeSH
Small hydrophobic gold nanoparticles with diameter lower than the membrane thickness can form clusters or uniformly distribute within the hydrophobic core of the bilayer. The coexistence of two stable phases (clustered and dispersed) indicates the energy barrier between nanoparticles. We calculated the distance dependence of the membrane-mediated interaction between two adjacent nanoparticles. In our model we consider two deformation modes: the monolayer bending and the hydroxycarbon chain stretching. Existence of an energy barrier between the clustered and the separated state of nanoparticles was predicted. Variation analysis of the membrane mechanical parameters revealed that the energy barrier between two membrane embedded nanoparticles is mainly the consequence of the bending deformation and not change of the thickness of the bilayer in the vicinity of nanoparticles. It is shown, that the forces between the nanoparticles embedded in the biological membrane could be either attractive or repulsive, depending on the mutual distance between them.
- MeSH
- chemické modely * MeSH
- hydrofobní a hydrofilní interakce MeSH
- kovové nanočástice chemie MeSH
- lipidové dvojvrstvy chemie MeSH
- shluková analýza MeSH
- termodynamika MeSH
- zlato chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- lipidové dvojvrstvy MeSH
- zlato MeSH
Lipid bilayer properties are quantified with a variety of arbitrary selected parameters such as molecular packing and dynamics, electrostatic potentials or permeability. In the paper we determined the effect of phloretin and 6-ketocholestanol (dipole potential modifying agents) on the membrane hydration and efficiency of the trans-membrane water flow. The dynamics of water molecules within the lipid bilayer interface was evaluated using solvent relaxation method, whereas the osmotically induced trans-membrane water flux was estimated with the stopped-flow method using the liposome shrinkage kinetics. The presence of phloretin or 6-ketocholestanol resulted in a change of both, the interfacial hydration level and osmotically driven water fluxes. Specifically, the presence of 6-ketocholestanol reduced the amount and mobility of water in the membrane interface. It also slows the osmotically induced water flow. The interfacial hydration change caused by phloretin was much smaller and the effect on osmotically induced water flow was opposite to that of 6-ketocholestanol.
- Klíčová slova
- Dipole potential, Lipid bilayer, Lipid bilayer dynamics, Solvent relaxation, Water permeability,
- MeSH
- floretin chemie MeSH
- fluorescenční barviva chemie MeSH
- ketocholesteroly chemie MeSH
- lipidové dvojvrstvy chemie metabolismus MeSH
- liposomy chemie metabolismus MeSH
- permeabilita MeSH
- simulace molekulární dynamiky * MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 6-ketocholestanol MeSH Prohlížeč
- floretin MeSH
- fluorescenční barviva MeSH
- ketocholesteroly MeSH
- lipidové dvojvrstvy MeSH
- liposomy MeSH
- voda MeSH
The interactions between haematoporphyrin (HP) and bilayer lipid membranes (BLM) were studied. A weak effect of HP on BLM conductivity was observed at HP concentrations ranging between 10(-6) and 3 x 10(-5) mol/l. Modulus of elasticity in the direction normal to the membrane plane (E perpendicular) and dynamic viscosity coefficient (eta) were measured, both exhibiting HP-induced decrease by 22-31% in the dark. In this case, membrane potential Vm became negative and reached a value close to -50 mV. Under illumination by low-intensity (1 mW) He-Ne laser (lambda = 632 nm) the values of parameters E perpendicular and eta of the HP-modified membranes increased by 41-66%, and Vm decreased to -20 mV. Upon removing HP from the solution by perfusion, irreversible changes in mechanical properties of the HP-modified membranes induced by the laser light were observed. The reason could be the formation of stable complexes of HP with the lipid molecules. HP binds to membrane noncooperatively, with a binding constant K approximately 10(5) l/mol.
Changes in the Young elasticity modulus in perpendicular direction to the membrane surface E perpendicular, in the coefficient of dynamic viscosity eta, in the electric capacitance C, in the surface charge U1, in the conductivity g and in the coefficient of non-linearity beta of current-voltage characteristic caused by insulin were studied in bilayer lipid membranes (BLM) prepared from a mixture of egg lecithin and cholesterol (4:1, w/w) in n-heptane. Even relatively small concentrations of insulin in electrolyte (ci approximately 4.8 x 10(-11) mol/l) caused a diminution in parameters E perpendicular and eta. Negative surface charge emerged on the membrane due to the insulin absorption, and U1 gradually increased depending on the concentration of the hormone in the electrolyte. Addition of insulin was also followed by an increase in membrane conductivity and affected the value of the coefficient of non-linearity beta of current-voltage characteristic. The effect of insulin on the BLM structure was discussed on the basis of the results obtained.
- MeSH
- elektrická vodivost MeSH
- inzulin farmakologie MeSH
- lipidové dvojvrstvy * MeSH
- membránové potenciály MeSH
- povrchové vlastnosti MeSH
- pružnost MeSH
- viskozita MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- inzulin MeSH
- lipidové dvojvrstvy * MeSH
