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Oxidative stress is a common feature of genetic and idiopathic neurological diseases that thus far have been intractable to drug therapy. Polyunsaturated fatty acids (PUFAs) form cellular, mitochondrial, retinal, and other membranes highly important in neuronal function. However, PUFAs are susceptible to the noxious lipid peroxidation (LPO) chain reaction, which is a common feature of various neurological and age-related pathologies, making this pathway an attractive target for therapeutic intervention. Regioselective deuteration that reinforces oxidation-prone, bis-allylic sites of PUFAs is a novel, nonantioxidant treatment modality that dramatically reduces LPO, potentially mitigating numerous diseases through preservation of membrane properties and amelioration of oxidative stress. Animal disease models and several ongoing human clinical trials highlight the potential of the deuterated-PUFA (D-PUFA) drug candidates currently in development. LPO of PUFAs is the worst type of oxidative damage because it is not stoichiometric but accretes exponentially, through its autocatalytic, chain reaction format. The slowest, rate-limiting step of the LPO process is a hydrogen atom abstraction off a bis-allylic (between double bonds) site. LPO is detrimental to lipid membranes, and is a common denominator of numerous neurological, mitochondrial and retinal diseases. Antioxidants cannot stop the LPO for several fundamental reasons. PUFAs are essential nutrients and have to be supplied with diet. Supplementing PUFAs deuterated at specific sites (D-PUFA drugs) to slow down LPO is a novel promising treatment modality for various neurological, mitochondrial and retinal diseases. [ABSTRACT FROM AUTHOR]

The formation of through pores in lipid bilayer membranes occurs in a number of cellular processes and is also applied for biotechnological and biomedical purposes. In the classical theory of pore formation, diffusion of membrane defects in space of radii is considered. When the first pore reaches a critical radius, the membrane irreversibly ruptures. It is usually presumed that the diffusion of defects occurs independently; their possible lateral interactions are not taken into account. In this paper, we consider a possible influence of lateral interactions of metastable through pores on their kinetics. It is assumed that the interaction occurs due to the overlap of elastic deformation fields arising at the edges of two pores. The interaction energy of two circular pores was calculated in the Derjaguin approximation for rapidly decaying potentials. The unidimensional potential of interaction of two linear parallel edges of pores formed in membranes of different lipid composition was calculated in the framework of the theory of elasticity of liquid crystals adapted to lipid membranes. It is shown that this interaction should lead to a considerable reduction of the measured line tension of the pore edge. In addition, the lifetime of two optimally situated metastable pores can increase approximately 10 times due to the interaction. Extrapolation of the obtained results to the case of a larger number of interacting pores makes it possible to predict an additional increase in the lifetime by one or two orders of magnitude. [ABSTRACT FROM AUTHOR]

Lipid membranes and their applications in analytical biochip devices represent a great tool for the study of membrane dynamics and the related biological phenomena. Lipid-membrane-assisted surface-sensitive sensors have employed to provide biological information as they improve molecular survivability as well as rule out incorrect signals arising from unwanted nonspecific binding between target molecules with sensor surfaces. To enhance the accuracy of the signal as well as the sensitivity of biochip sensors, a variety of strategies have been employed. Here, we introduce various types of in vitro model membrane platforms/techniques and discuss current challenges in the lipid-membrane-assisted surface-sensitive analytical sensors application. [ABSTRACT FROM AUTHOR]

Reducing the amount of carbon emissions has been a formidable challenge especially to countries experiencing rapid economic growth. This prompted the development of various materials and methodologies to capture emissions to address climate change. The current study aimed to contribute in the development of carbon dioxide capture through the biological approach by using microorganisms such as microalgae. Biological fixation involving microalgae involves a complex process that has not been fully understood as current experimental methods can only deliver analysis on a macroscopic scale. The study demonstrated the dynamics of carbon dioxide molecules in the atomic scale using molecular dynamics. The permeation coefficient of carbon dioxide molecules was calculated at different range of temperature and salinity using the inhomogeneous solubility diffusion model. The GROMOS53a6 and SPC force field was used for the interaction of molecules. Moreover, the force autocorrelation function was used to calculate the diffusion coefficient. The resulting diffusion coefficients were in a good agreement with experimental data. The highest permeation coefficient of 2.3994 × 10−3 cm s−1 was calculated at 330 K 0.55 M conditions. Due to the nonpolar nature of carbon dioxide molecule, the mobility as it permeates inside the bilayer was not affected. Hence, the study suggests that the temperature and salinity does not prevent nor significantly affects the permeability of microalgae lipid membrane from carbon dioxide molecules. [ABSTRACT FROM AUTHOR]

Oseltamivir belongs to the neuraminidase inhibitors, developed against the influenza virus, and registered under the trademark Tamiflu. Despite its long-term acquaintance, there is limited information in the literature about its physicochemical and structural properties in a lipid-water system. We present an experimentally determined partition coefficient with structural information on the interaction of oseltamivir with the model membrane, its possible location, and its effect on the membrane thermodynamics. The hydrophobic part of the lipid bilayer is affected to a moderate extent, which was proved by slight changes in thermal and structural properties. Hereby, interaction of oseltamivir with the phospholipid bilayer induces concentration dependent decrease of lateral pressure in the bilayer acyl chain region. Oseltamivir charges the bilayer surface positively, which results in the zeta potential increase and changes in anisotropic properties studied by the polarised light microscopy. At the highest oseltamivir concentrations studied, the multilamellar structure is extensively disturbed, likely due to electrostatic repulsion between the adjacent bilayers. [Display omitted] • Experimental partition coefficient of oseltamivir in lipid water system is 312. • Lateral pressure experiments revealed biphasic binding. • Oseltamivir moderately charges the membrane. • The charge of the bilayers causes a loose correlation between the lamellae. [ABSTRACT FROM AUTHOR]

Vesicular trafficking facilitates material transport between membrane-bound organelles. Membrane protein cargos are trafficked for relocation, recycling, and degradation during various physiological processes. In vitro fusion studies utilized synthetic lipid membranes to study the molecular mechanisms of vesicular trafficking and to develop synthetic materials mimicking the biological membrane trafficking. Various fusogenic conditions which can induce vesicular fusion have been used to establish synthetic systems that can mimic biological systems. Despite these efforts, the mechanisms underlying vesicular trafficking of membrane proteins remain limited and robust in vitro methods that can construct synthetic trafficking systems for membrane proteins between large membranes (>1 μm2) are unavailable. Here, we provide data to show the spontaneous transfer of small membrane-bound peptides (∼4 kD) between a supported lipid bilayer (SLB) and giant unilamellar vesicles (GUVs). We found that the contact between the SLB and GUVs led to the occasional but notable transfer of membrane-bound peptides in a physiological saline buffer condition (pH 7.4, 150 mM NaCl). Quantitative and dynamic time-lapse analyses suggested that the observed exchange occurred through the formation of hemi-fusion stalks between the SLB and GUVs. Larger protein cargos with a size of ∼77 kD could not be transferred between the SLB and GUVs, suggesting that the larger-sized cargos limited diffusion across the hemi-fusion stalk, which was predicted to have a highly curved structure. Compositional study showed Ni-chelated lipid head group was the essential component catalyzing the process. Our system serves as an example synthetic platform that enables the investigation of small-peptide trafficking between synthetic membranes and reveals hemi-fused lipid bridge formation as a mechanism of peptide transfer. [Display omitted] [ABSTRACT FROM AUTHOR]

Plasmon waveguide resonance (PWR) is a variant of surface plasmon resonance (SPR) that was invented about two decades ago at the University of Arizona. In addition to the characterization of the kinetics and affinity of molecular interactions, PWR possesses several advantages relative to SPR, namely, the ability to monitor both mass and structural changes. PWR allows anisotropy information to be obtained and is ideal for the investigation of molecular interactions occurring in anisotropic-oriented thin films. In this review, we will revisit main PWR applications, aiming at characterizing molecular interactions occurring (1) at lipid membranes deposited in the sensor and (2) in chemically modified sensors. Among the most widely used applications is the investigation of G-protein coupled receptor (GPCR) ligand activation and the study of the lipid environment’s impact on this process. Pioneering PWR studies on GPCRs were carried out thanks to the strong and effective collaboration between two laboratories in the University of Arizona leaded by Dr. Gordon Tollin and Dr. Victor J. Hruby. This review provides an overview of the main applications of PWR and provides a historical perspective on the development of instruments since the first prototype and continuous technological improvements to ongoing and future developments, aiming at broadening the information obtained and expanding the application portfolio.

Cell membranes are heterogeneous in lipid composition which leads to the phase separation with the formation of nanoscopic liquid-ordered domains, also called rafts. There are multiple cell processes whereby the clustering of these domains into a larger one might be involved, which is responsible for such important processes as signal transduction, polarized sorting, or immune response. Currently, antimicrobial amphipathic peptides are considered promising antimicrobial, antiviral, and anticancer therapeutic agents. Here, within the framework of the classical theory of elasticity adapted for lipid membranes, we investigate how the presence of the peptides in a phase-separated membrane influences the fusion of the domains. We show that the peptides tend to occupy the boundaries of liquid-ordered domains and significantly increase the energy barrier of the domain-domain fusion, which might lead to misregulation of raft clustering and adverse consequences for normal cell processes.

With the aim of better understanding the nature of metabolism in the first cells and the relationship between the origin of life and the origin of metabolism, we propose three criteria that a chemical reaction system must satisfy in order to constitute a metabolism that would be capable of sustaining growth and division of a protocell. (1) Biomolecules produced by the reaction system must be maintained at high concentration inside the cell while they remain at low or zero concentration outside. (2) The total solute concentration inside the cell must be higher than outside, so there is a positive osmotic pressure that drives cell growth. (3) The metabolic rate (i.e., the rate of mass throughput) must be higher inside the cell than outside. We give examples of small-molecule reaction systems that satisfy these criteria, and others which do not, firstly considering fixed-volume compartments, and secondly, lipid vesicles that can grow and divide. If the criteria are satisfied, and if a supply of lipid is available outside the cell, then continued growth of membrane surface area occurs alongside the increase in volume of the cell. If the metabolism synthesizes more lipid inside the cell, then the membrane surface area can increase proportionately faster than the cell volume, in which case cell division is possible. The three criteria can be satisfied if the reaction system is bistable, because different concentrations can exist inside and out while the rate constants of all the reactions are the same. If the reaction system is monostable, the criteria can only be satisfied if there is a reason why the rate constants are different inside and out (for example, the decay rates of biomolecules are faster outside, or the formation rates of biomolecules are slower outside). If this difference between inside and outside does not exist, a monostable reaction system cannot sustain cell growth and division. We show that a reaction system for template-directed RNA polymerization can satisfy the requirements for a metabolism, even if the small-molecule reactions that make the single nucleotides do not.

A better elucidation of molecular mechanisms underlying drug-membrane interaction is of great importance for drug research and development. To date, different biochemical and biophysical methods have been developed to study biological membranes at molecular level. This review focuses on the recent applications and achievements of modern analytical techniques in the study of drug interactions with lipid membranes, including chromatography, spectrometry, calorimetry, and acoustic sensing. The merits and limitations of these techniques were compared and critically discussed. Moreover, various types of biomimetic model membranes including liposomes, lipid monolayers, and supported lipid monolayers/bilayers were described. General mechanisms underlying drug-membrane interaction process were also briefly introduced.

The increase in atmospheric oxygen levels imposed significant environmental pressure on primitive organisms concerning intracellular oxygen concentration management. Evidence suggests the rise of cholesterol, a key molecule for cellular membrane organization, as a cellular strategy to restrain free oxygen diffusion under the new environmental conditions. During evolution and the increase in organismal complexity, cholesterol played a pivotal role in the establishment of novel and more complex functions associated with lipid membranes. Of these, caveolae, cholesterol-rich membrane domains, are signaling hubs that regulate important in situ functions. Evolution resulted in complex respiratory systems and molecular response mechanisms that ensure responses to critical events such as hypoxia facilitated oxygen diffusion and transport in complex organisms. Caveolae have been structurally and functionally associated with respiratory systems and oxygen diffusion control through their relationship with molecular response systems like hypoxia-inducible factors (HIF), and particularly as a membrane-localized oxygen sensor, controlling oxygen diffusion balanced with cellular physiological requirements. This review will focus on membrane adaptations that contribute to regulating oxygen in living systems.

Abstract: Pore-forming peptides are of interest due to their antimicrobial activity and ability to form gateways through lipid membranes. Chemical modification of these peptides makes it possible to arrange several peptide monomers into well-defined pore-forming structures using various templating strategies. These templated super-structures can exert antimicrobial activity at significantly lower total peptide concentration than their untemplated equivalents. In addition, the chemical moieties used for templating may be functionalized to interact specifically with targeted membranes such as those of pathogens or cancer cells. A range of molecular templates has been explored, including dimerization of pore-forming monomers, their covalent attachment to cyclodextrin, porphyrin or fullerene scaffolds as well as attachment of amino acid linkers or nucleic acid constructs to generate assemblies of 4 to 26 peptides or proteins. Compared to free peptide monomers, templated pore assemblies showed increased membrane affinity, prolonged open-state lifetimes of the pores and more frequent pore formation due to higher local concentration. These constructs are useful model systems for biophysical studies to understand porin and ion channel proteins and their mechanisms of insertion into lipid membranes. Recently designed DNA-templates are expanding the usefulness of templated pore assemblies beyond applications of cell killing and may include targeted drug delivery and accelerate the emerging field of single-molecule detection and characterization of biomolecules by nanopore-based resistive pulse sensing.

Most biological membranes are curved, and both lipids and proteins play a role in generating curvature. For any given membrane shape and composition, it is not trivial to determine whether lipids are laterally distributed in a homogeneous or inhomogeneous way, and whether the inter-leaflet distribution is symmetric or not. Here we present a simple computational tool that allows to predict the preference of any lipid type for membranes with positive vs. negative curvature, for any given value of curvature. The tool is based on molecular dynamics simulations of tubular membranes with hydrophilic pores. The pores allow spontaneous, barrierless flip-flop of most lipids, while also preventing differences in pressure between the inner and outer water compartments and minimizing membrane asymmetric stresses. Specifically, we provide scripts to build and analyze the simulations. We test the tool by performing simulations on simple binary lipid mixtures, and we show that, as expected, lipids with negative intrinsic curvature distribute to the tubule inner leaflet, the more so when the radius of the tubular membrane is small. Compared to other existing computational methods, relying on membrane buckles and tethers, our method is based on spontaneous inter-leaflet transport of lipids, and therefore allows to explore lipid distribution in asymmetric membranes. The method can easily be adapted to work with any molecular dynamics code and any force field., (Copyright © 2024. Published by Elsevier Inc.)

• Hydration of model membrane based on ceramide [AP] in the DMSO, urea and ethanol aqueous solutions was investigated. • Urea and DMSO slow down the membrane swelling in aqueous solution. • Urea and DMSO at high concentrations reduce of repeat distance of fully hydrated membrane. Hydration of oriented multilamellar membrane based on ceramide [AP] in the DMSO, urea and ethanol aqueous solutions at various solute concentrations was investigated by neutron diffraction. Neither urea nor DMSO influence the repeat distance of the membrane and internal structure of bilayer at their mole concentration of up to 0.15 and 0.10, respectively. The d -spacing reduction effect of both compounds was observed at their concentrations of 0.2 for urea and 0.2 and 0.4 for DMSO. Compared to hydration in the pure water, both urea and DMSO slow down the swelling process, and this slowdown is more pronounced with increasing in their concentration. At concentration of 0.2, urea and DMSO induce the slight phase separation of the fully hydrated samples; at the highest used concentration of 0.6, DMSO induces the strong time-depend separation of the sample probably due to fluidization of lipid bilayers. Ethanol at a used molar concentration of 0.03 leads to dissolution of the sample. [ABSTRACT FROM AUTHOR]

Understanding the molecular mechanism underlying pore formation in lipid membranes by antimicrobial peptides is of great importance in biological sciences as well as in drug design applications. Melittin has been widely studied as a pore forming peptide, though the molecular mechanism for pore formation is still illusive. We examined the free energy barrier for the creation of a pore in lipid membranes with and without multiple melittin peptides. It was found that six melittin peptides significantly stabilized a pore, though a small barrier (a few k B T) for the formation still existed. With five melittin peptides or fewer, the pore formation barrier was much higher, though the established pore was in a local energy minimum. Although seven melittins effectively reduced the free energy barrier, a single melittin peptide left the pore after a long time MD simulation probably because of the overcrowded environment around the bilayer pore. Thus, it is highly selective for the number of melittin peptides to stabilize the membrane pore, as was also suggested by the line tension evaluations. The free energy cost required to insert a single melittin into the membrane is too high to explain the one-by-one insertion mechanism for pore formation, which also supports the collective melittin mechanism for pore formation. Unlabelled Image • The free energy minima at stable pore states are found in the presence of 4, 5, 6, and 7 melittin peptides on the lipid bilayer. • The free energy barrier for a collective pore formation by 6 and 7 melittin peptides is only a few kBT. • The radius of a pore formed by six melittin peptides in the MD simulation corresponds to that observed experimentally. • A collective pore formation is a more likely process to form a membrane pore by multiple melittin peptides than one-by-one melittin insertion. [ABSTRACT FROM AUTHOR]

It is believed that separation of lipid matrix of biological membranes into ordered and disordered phases plays an important role in the lateral distribution of proteins and transduction of cellular signals through the plasma membrane. In model lipid membranes with symmetric composition of monolayers, such phase separation always leads to formation of bilayer domains. However, the lipid composition of outer and inner monolayers of plasma membranes of cells is different, i.e., these membranes are asymmetric. The mechanism of coupling of monolayer domains into bilayer structures in cells still remains unexplained. The ordered lipid domain is thicker than the surrounding membrane; as a result, elastic deformations occur at their boundary. Minimization of the elastic part of the boundary energy contributes to the coupling of monolayer domains in opposite monolayers. However, this driving force is not enough to ensure that domains will come into register: at a certain fraction of the membrane area occupied by the domains, the elastic energy can reach the minimum in antisymmetric configurations (the ordered domain in the upper monolayer is opposed by disordered monolayer of the surrounding membrane). As an alternative factor of the coupling, we considered curvature thermal fluctuations of the membrane shape. Our theoretical analysis of elastic deformations in a lipid bilayer that is asymmetric in monolayer composition shows that more rigid lipid domains tend to distribute into the region with lower curvature of the monolayer; these regions naturally coincide in opposite monolayers. Thus, the coupling of ordered domains in different monolayers is provided by their greater bending stiffness as compared to the surrounding membrane. At the same time, greater ordering leads to lateral condensation, i.e., to the decrease of the average area per lipid molecule. The difference in area per lipid molecule in the coexisting membrane phases, on the contrary, tends to separate bilayer domains into their monolayer components. To quantify the coupling energy of ordered domains, it is necessary to take both of these effects into account. [ABSTRACT FROM AUTHOR]

Dynamin proteins assemble into characteristic helical structures around necks of clathrin-coated membrane buds. Hydrolysis of dynamin-bound GTP results in both fission of the membrane neck and partial disruption of the dynamin oligomer. Imaging by atomic force microscopy reveals that, on GTP hydrolysis, dynamin oligomers undergo a dynamic remodeling and lose their distinctive helical shape. While breakup of the dynamin helix is a critical stage in clathrin-mediated endocytosis, the mechanism for this remodeling of the oligomer has not been resolved. In this paper, we formulate an analytical, elasticity-based model for the reshaping and disassembly of the dynamin scaffold. We predict that the shape of the oligomer is modulated by the orientation of dynamin's pleckstrin homology (PH) domain relative to the underlying membrane. Our results indicate that tilt of the PH domain drives deformation and fragmentation of the oligomer, in agreement with experimental observations. This model motivated the introduction of the tilted helix: a curve that maintains a fixed angle between its normal and the normal of the embedding surface. Our findings highlight the importance of tilt as a key regulator of size and morphology of membrane-bound oligomers. [ABSTRACT FROM AUTHOR]

• Improving stability of DNA nanostructures in biological relevant fluids. • Methods for interfacing DNA nanostructures with lipid membranes are reviewed. • DNA nanostructures can mimic, target and control membrane proteins. • Synthetic membrane channels made of DNA are reviewed. • DNA nanostructures can control the shape of lipid membranes. Recent developments in DNA nanotechnology brought rich structural and functional diversity. However, for DNA nanostructures to perform in a biologically relevant context, obstacles such as nuclease activity and low divalent ion concentrations have to be addressed. For drug delivery or gene therapy applications, ultimately the lipid membrane barriers must be targeted and overcome. In this article, we highlight efforts and achievements in enhancing the stability of DNA nanostructures including chemical modifications, covalent crosslinking and coating with protective layers composed of polymers or lipids. We then review interactions between DNA nanostructures and lipid membranes, which are often mediated by ligands for membrane receptors or hydrophobic domains incorporated into the structure. Finally, we present applications of DNA nanostructures on and in lipid membranes, including higher order assembly, controlling membrane curvature, targeting and arranging membrane proteins in living cells and DNA-based synthetic lipid channels. [ABSTRACT FROM AUTHOR]

Synthetic polymers mimicking antimicrobial peptides have drawn considerable interest as potential therapeutics. N-substituted glycines, or peptoids, are recognized by their in vivo stability and ease of synthesis. Peptoids are thought to act primarily on the negatively charged lipids that are abundant in bacterial cell membranes. A mechanistic understanding of lipid-peptoid interaction at the molecular level will provide insights for rational design and optimization of peptoids. Here, we highlight recent studies that utilize synchrotron liquid surface X-ray scattering to characterize the underlying peptoid interactions with bacterial and eukaryotic membranes. Cellular membranes are highly complex, and difficult to characterize at the molecular level. Model systems including Langmuir monolayers, are used in these studies to reduce system complexity. The general workflow of these systems and the corresponding data analysis techniques are presented alongside recent findings. These studies investigate the role of peptoid physicochemical characteristics on membrane activity. Specifically, the roles of cationic charge, conformational constraint via macrocyclization, and hydrophobicity are shown to correlate their membrane interactions to biological activities in vitro. These structure-activity relationships have led to new insights into the mechanism of action by peptoid antimicrobials, and suggest optimization strategies for future therapeutics based on peptoids. [ABSTRACT FROM AUTHOR]

Abstract An effect of β-carotene and its polar derivative, zeaxanthin, on a concentration of singlet oxygen in lipid membranes was studied in a model system. The carotenoids were incorporated into the membranes of small unilamellar liposomes at a concentration of 0.15 mol% with respect to lipid. Singlet oxygen was generated in a liposome suspension via photosensitization of toluidine blue, and its concentration in a membrane was detected with application of a specific fluorescence probe (singlet oxygen sensor green reagent) located in the lipid bilayer. The results show the carotenoid-dependent decrease in the concentration of singlet oxygen in the membranes formed with unsaturated lipids (egg yolk phosphatidylcholine and digalactosyldiacylglycerol) but not in the case of the membranes formed with a saturated lipid (dimyristoylphosphatidylcholine). The effect of carotenoids was about twice as high as in the case of cholesterol present in liposomes at the same concentration. The results suggest that carotenoids protect membranes formed with unsaturated lipids against singlet oxygen through combined activity of different mechanisms: modification of structural properties of the lipid bilayers, physical quenching of singlet oxygen and chemical reactions leading to the pigment oxidation. The latter conclusion is based on the analysis of the absorption spectra of liposomes before and after light exposure. An importance of the different modes of protection by carotenoids against single oxygen toxicity towards biomembranes is discussed. Graphical abstract Unlabelled Image Highlights • Carotenoids decrease concentration of singlet oxygen in lipid bilayers formed with unsaturated lipids. • The protection mechanism of Zeaxanthin and β-Carotene against the attack of singlet oxygen is different. • Zeaxanthin shows greater chemical stability than β-Carotene in model membranes exposed to singlet oxygen. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Glycyrrhizic acid (GA), saponin of licorice shows wide range of biological activity. • Mechanism of GA activity on the cell and molecular level is rarely discussed. • GA activity could be caused by the cell membrane modification. Abstract Glycyrrhizic acid is the main active component of Licorice root which has been known in traditional Chinese and Japanese medicine since ancient times. In these cultures glycyrrhizic acid (GA) is one of the most frequently used drugs. However, only in 21-st century a novel unusual property of the GA to enhance the activity of other drugs has been discovered. The review describes briefly the experimental evidences of wide spectrum of own biological activities of glycyrrhizic acid as well as discusses the possible mechanisms of the ability of GA to enhance the activity of other drugs. We have shown that due to its amphiphilic nature GA is able to form self-associates in aqueous and non-aqueous media, as well as water soluble complexes with a wide range of lipophilic drugs. The main purpose of our review is to focus reader's attention on physicochemical studies of the molecular mechanisms of GA activity as a drug delivery system (DDS). In our opinion, the most intriguing feature of glycyrrhizic acid which might be the key factor in its therapeutic activity is the ability of GA to incorporate into the lipid bilayer and to increase the membrane fluidity and permeability. The ability of biomolecules and their aggregates to change the properties of cell membranes is of great significance, from both fundamental and practical points of view. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The exposure of biological membranes to reactive oxygen species (ROS) plays an important role in many pathological conditions such as inflammation, infection, or sepsis. ROS also modulate signaling processes and produce markers for damaged tissue. Lipid peroxidation, mainly affecting polyunsaturated phospholipids, results in a complex mixture of oxidized products, which may dramatically alter membrane properties. Here, we have employed a set of biophysical and surface-chemical techniques, including neutron and X-ray scattering, to study the structural, compositional, and stability changes due to oxidative stress on phospholipid bilayers composed of lipids with different degrees of polyunsaturation. In doing so, we obtained real-time information about bilayer degradation under in situ UV exposure using neutron reflectometry. We present a set of interrelated physicochemical effects, including gradual increases in area per molecule, head group and acyl chain hydration, as well as bilayer thinning, lateral phase separation, and defect formation leading to content loss upon membrane oxidation. Such effects were observed to depend on the presence of polyunsaturated phospholipids in the lipid membrane, suggesting that these may also play a role in the complex oxidation processes occurring in cells. [ABSTRACT FROM AUTHOR]

Abstract In the direct cell membrane penetration, arginine-rich cell-penetrating peptides are thought to penetrate into cells across the hydrophobic lipid membranes. To investigate the effect of the amphipathic property of arginine-rich peptide on the cell-penetrating ability, we designed a novel amphipathic cell-penetrating peptide, A2-17, and its derivative, A2-17KR, in which all lysine residues are substituted with arginine residues, based on the glycosaminoglycan binding region in the N-terminal α-helix bundle of human apolipoprotein E. Isothermal titration calorimetry showed that A2-17 variants have a strong ability to bind to heparin with high affinity. Circular dichroism and tryptophan fluorescence measurements demonstrated that A2-17 variants bind to lipid vesicles with a structural change from random coil to amphipathic α-helix, being inserted into the hydrophobic membrane interiors. Flow cytometric analysis and confocal laser scanning microscopy demonstrated the great cell penetration efficiency of A2-17 variants into CHO-K1 cells when incubated at low peptide concentrations (2 μM or less), suggesting that the increased amphipathicity with α-helix formation enhances the cell membrane penetration ability of arginine-rich peptides. Interestingly, A2-17KR exhibited lower efficiency of cell membrane penetration compared to A2-17 despite of their similar binding affinity to lipid membranes. Since high peptide concentrations (typically >10 μM) are usually prerequisite for efficient cell penetration of arginine-rich peptides, A2-17 is a unique amphipathic cell-penetrating peptide that exhibits an efficient cell penetration ability even at low peptide concentrations. Graphical abstract Unlabelled Image Highlights • An amphipathic cell-penetrating peptide, A2-17, is newly designed. • A2-17 binds to both heparin and lipid membranes with high affinity. • A2-17 forms amphipathic α-helix upon binding to heparin and lipid membranes. • A2-17 efficiently penetrates cell membranes even at low peptide concentrations. [ABSTRACT FROM AUTHOR]

Graphical abstract Relationship between pressure and the retention time of AMPs measured from HPLC and implications to membrane-lytic activity and cell selectivity. Abstract Many short cationic peptides are amphiphilic and are often termed antimicrobial peptides (AMPs) as they can kill various microorganisms. These AMPs have largely been discovered from nature, but over the past two decades many biomimetic and de novo designed AMPs have been reported, offering a huge variety of attractive properties for further exploitation. Under the current global endeavour of fighting against antimicrobial resistance, it is useful to introduce AMPs to the biointerface research community and compare their modes of action with conventional antibiotics. Because natural AMPs often have long sequences and other biological functions implicated, they can't be used as antimicrobial agents. However, rational AMP design helps eliminate their shortcomings and more importantly, optimise their structure-function relationship. This review will first introduce the key approaches recently utilised in structural design of AMPs and then introduce the main lipid membrane models such as spread lipid monolayers and vesicles together with the characterisation techniques adopted in early AMP design and development. These studies are crucial towards understanding key factors affecting their efficacy and toxicity. Thus, various interfacial measurements facilitated by different forms of lipid monolayers and bilayers provide valuable support to the selective responses of AMPs to different cell types used in bactericidal assays and cytotoxicity tests, emphasising the link between molecular models and cell models. A number of clinical trials of AMPs have been either under way or completed, demonstrating the huge potential of AMPs in a range of applications. [ABSTRACT FROM AUTHOR]

Introduction: AA amyloidosis develops as a result of prolonged inflammation and is characterized by deposits of N-terminal proteolytic fragments of the acute phase reactant serum amyloid A (SAA). Macrophages are usually found adjacent to amyloid, suggesting their involvement in the formation and/or degradation of the amyloid fibrils. Furthermore, accumulating evidence suggests that lipid membranes accelerate the fibrillation of different amyloid proteins. Methods: Using an experimental mouse model of AA amyloidosis, we compared the amyloidogenic effect of liposomes and/or amyloid-enhancing factor (AEF). Inflammation was induced by subcutaneous injection of silver nitrate followed by intravenous injection of liposomes and/or AEF to accelerate amyloid formation. Results: We showed that liposomes accelerate amyloid formation in inflamed mice, but the amyloidogenic effect of liposomes was weaker compared with AEF. Regardless of the induction method, amyloid deposits were mainly found in the marginal zones of the spleen and coincided with the depletion of marginal zone macrophages, while red pulp macrophages and metallophilic marginal zone macrophages proved insensitive to amyloid deposition. Conclusions: We conclude that increased intracellular lipid content facilitates AA amyloid fibril formation and show that the mouse model of AA amyloidosis is a suitable system for further mechanistic studies. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Chlorophyll a was incorporated into DMPC/DHPC assemblies. • J-aggregate of chlorophyll a was induced in DMPC/DHPC = 3:2 (q = 1.5). • Local hydrophobicity around chlorophyll a was analyzed based on the deconvolution of Soret band spectrum. • Photo-reduction of methyl viologen can be catalyzed by aggregated chlorophyll a. Abstract The J-aggregate of chlorophyll a (Chl a) functions as a light-harvesting antenna in natural systems. In this study, we employed the phospholipid membranes composed of longer-chain 1,2-dimyristoyl- sn -glycero-3-phosphocholine (DMPC) and shorter-chain 1,2-dihexanoyl- sn -glycero-3-phosphocholine (DHPC), as a platform to induce Chl a aggregates. The DMPC/DHPC assembly at the mixing ratio (q) = 1.5 induced J-aggregates of Chl a at 20 °C with a total lipid concentration of 20 mM. While, Chl a aggregates were not observed in the membranes at q = ∞ (DMPC vesicles) and q = 0 (DHPC micelles). The surroundings Chl a molecules in DMPC/DHPC at q = 1.5 were estimated to comprise a less polar environment, based on the deconvolution analysis of Soret band spectrum (400–440 nm). The photo-reduction activity of Chl a J-aggregates was investigated in lower lipid concentration conditions. [ABSTRACT FROM AUTHOR]

Intrauterine Contraceptive Devices with multifaceted application potential is a need of an hour. Although, copper-based IUDs exert an effective contraceptive as well as anticancer effects in a long-term basis, but also results in multiple complications. In this regard, RISUG® a polymer based contraceptive device has been introduced as a suitable alternative. However, its potential to impart protective effects against development of endometrial cancer still remains unexplored. This article presents the hypothesis on this unexplored domain and provides scientific facts to support the hypothesis. The mechanism of anticancerous activity is hypothesized that RISUG® involves its lipid membrane destabilizing activity. This activity is modulated by both, the cellular microenvironment and lipid bilayer composition. Acidic environment along with the significantly higher fluidic nature of lipid bilayer of the cancerous cells make them more prone to lipid solubilisation effect of RISUG®. We here present an in-depth insight into the factors that would favour faster solubilisation of cancer cell membrane, thereby exerting an anticancer effect. [ABSTRACT FROM AUTHOR]

Abstract Soluble oligomers of prion proteins (PrP), produced during amyloid aggregation, have emerged as the primary neurotoxic species, instead of the fibrillar end-products, in transmissible spongiform encephalopathies. However, whether the membrane is among their direct targets, that mediate the downstream adverse effects, remains a question of debate. Recently, questions arise from the formation of membrane-active oligomeric species generated during the β-aggregation pathway, either in solution, or in lipid environment. In the present study, we characterized membrane interaction of off-pathway oligomers from recombinant prion protein generated along the amyloid aggregation and compared to lipid-induced intermediates produced during lipid-accelerated fibrillation. Using calcein-leakage assay, we show that the soluble prion oligomers are the most potent in producing leakage with negatively charged vesicles. Binding affinities, conformational states, mode of action of the different PrP assemblies were determined by thioflavin T binding-static light scattering experiments on DOPC/DOPS vesicles, as well as by FTIR-ATR spectroscopy and specular neutron reflectivity onto the corresponding supported lipid bilayers. Our results indicate that the off-pathway PrP oligomers interact with lipid membrane via a distinct mechanism, compared to the inserted lipid-induced intermediates. Thus, separate neurotoxic mechanisms could exist following the puzzling intermediates generated in the different cell compartments. These results not only reveal an important regulation of lipid membrane on PrP behavior but may also provide clues for designing stage-specific and prion-targeted therapy. Graphical abstract Unlabelled Image Highlights • Off-pathway PrP oligomers interact with PC/PS bilayer by destabilization of the entire membrane. • Lipid-induced PrP on-pathway intermediates are inserted in the PC/PS bilayer. • Off-pathway and lipid-induced on-pathway oligomers are distinctly β-sheeted. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Interactions between valproic acid and lipid bilayers were elucidated by using electrochemical and spectroscopic techniques. • Valproic acid incorporation into the lipid vesicles results in an increase in the packing density of the acylic chains. • Valproic acid affects permeability and structural properties of the membrane by inducing the formation of film defects. Abstract Lipid bilayers of 1,2-dimyristoyl- sn -glycero-3-phosphocholine (DMPC) were prepared in two forms, as a suspension of multilamellar spherical vesicles and as planar membranes deposited on a conductive solid support. We used Fourier Transformed Infrared (FTIR) and Raman spectroscopic techniques to study the lipid vesicles while the solid supported bilayers were characterized by using electrochemical experiments (cyclic voltammetry and impedance). Valproic acid (Valp) was either present in the solution or incorporated into the lipid structure. As the Valp:DMPC ratio increases the phase transition temperature decreases while the phase transition becomes less marked. Moreover, for the Valp:DMPC complex species a slight decrease in the number of gauche isomers was observed relative to the number of trans isomers what corresponds to an increase in the packing density of the acylic chains. Based on derived electrical properties of the supported membranes it can be concluded that Valp induces the formation of pores and other defects in the lipid films. Valp incorporated into the membrane is seriously detrimental to the bilayer stability. [ABSTRACT FROM AUTHOR]

Ellagitannins have antimicrobial activity, which might be related to their interactions with membrane lipids. We studied the interactions of 12 different ellagitannins and pentagalloylglucose with a lipid extract of Escherichia coli by high-resolution magic angle spinning NMR spectroscopy. The nuclear Overhauser effect was utilized to measure the cross relaxation rates between ellagitannin and lipid protons. The shifting of lipid signals in 1H NMR spectra of ellagitannin–lipid mixture due to ring current effect was also observed. The ellagitannins that showed interaction with lipids had clear structural similarities. All ellagitannins that had interactions with lipids had glucopyranose cores. In addition to the central polyol, the most important structural feature affecting the interaction seemed to be the structural flexibility of the ellagitannin. Even dimeric and trimeric ellagitannins could penetrate to the lipid bilayers if their structures were flexible with free galloyl and hexahydroxydiphenoyl groups.

[Display omitted] • Elevated Fullerenol concentration leads to clustering, reducing lipid interaction and fostering surface aggregation on the membrane. • Fullerenol addition enhances DOPC/CHOL(30%) membrane stiffness, decreasing lipid mobility and area occupancy. • Partial penetration in polar membrane region; potential molecular anchoring on the hydrated lipid membrane surface. In this work, the physical–chemical properties of lipid membranes interacting with Fullerenol-C 60 (OH) 24 molecules immersed in an aqueous solution were studied using Molecular Dynamics (MD) simulations. In order to analyze the role played by the concentration of Fullerene-C 60 (OH) 24 in the interaction with lipid membranes, we carried out simulations with variations in the number (n = 1, 2, 4, 8, 12, 16 or 20) of Fullerene-C 60 (OH) 24 molecules present in the solution in which the lipid membrane was immersed. The lipid membrane simulated was composed of DOPC (dipalmitoylphosphatidylcholine) with 30% of cholesterol molecules (DOPC/CHOL(30%)). The average behavior of the Coulomb and vdW interaction energy shows that as the Fullerenol-C 60 (OH) 24 molecules concentration increases, insertion of Fullerenol in the lipid bilayer becomes energetically unfavorable since they tend to interact with each other, leading to the formation of clusters. From the mass density, we confirmed that there is a decrease in the insertion of Fullerenol-C 60 (OH) 24 molecules in the bilayer as n increases. We noticed that Fullerenol molecules get closer to each other and are deposited on the surface of the lipid bilayers but do not penetrate them. The diffusion coefficient (MSD) reveals a decrease in the mobility of Fullerenol molecules as n increases. This observation confirms the agglomeration of Fullerenol on the lipid membrane's surface. A detailed analysis of hydrogen bonds (HB) involving Fullerenol–Fullerenol, Fullerenol–DOPC, and Fullerenol–Water pairs provides insight into this phenomenon. While the average number of HBs in the Fullerenol–Water pair remains relatively constant as n increases, there is a significant increase in HB interactions for the Fullerenol–Fullerenol pair. In contrast, the Fullerenol–DOPC pair experiences a decrease in HBs, underscoring the preference of Fullerenol to agglomerate and deposit onto the lipid membrane's surface. [ABSTRACT FROM AUTHOR]

There is a growing interest in the use of microbial cell factories to produce butanol, an industrial solvent and platform chemical. Biobutanol can also be used as a biofuel and represents a cleaner and more sustainable alternative to the use of conventional fossil fuels. Solventogenic Clostridia are the most popular microorganisms used due to the native expression of butanol synthesis pathways. A major drawback to the wide scale implementation and development of these technologies is the toxicity of butanol. Various membrane properties and related functions are perturbed by the interaction of butanol with the cell membrane, causing lower yields and higher purification costs. This is ultimately why the technology remains underemployed. This study aimed to develop a deeper understanding of butanol toxicity at the membrane to determine future targets for membrane engineering. Changes to the lipidome in Clostridium saccharoperbutylacetonicum N1–4 (HMT) throughout butanol fermentation were investigated with thin layer chromatography and mass spectrometry. By the end of fermentation, levels of phosphatidylglycerol lipids had increased significantly, suggesting an important role of these lipid species in tolerance to butanol. Using membrane models and in vitro assays to investigate characteristics such as permeability, fluidity, and swelling, it was found that altering the composition of membrane models can convey tolerance to butanol, and that modulating membrane fluidity appears to be a key factor. Data presented here will ultimately help to inform rational strain engineering efforts to produce more robust strains capable of producing higher butanol titres. [Display omitted] • Butanol causes membrane damage through intercalation and pore formation. • The Clostridial lipidome changes significantly during butanol fermentation. • The ratio of PE:PG headgroups appears important for butanol tolerance. • This reveals targets for future membrane engineering strategies. [ABSTRACT FROM AUTHOR]

Ionic liquids (ILs) have been emerged as a versatile class of compounds that can be easily tuned to achieve desirable properties for various applications. The ability of ILs to interact with biomembranes has attracted significant interest, as they have been shown to modulate membrane properties in ways that may have implications for various biological processes. This review provides an overview of recent studies that have investigated the interaction between ILs and biomembranes. We discuss the effects of ILs on the physical and chemical properties of biomembranes, including changes in membrane fluidity, permeability, and stability. We also explore the mechanisms underlying the interaction of ILs with biomembranes, such as electrostatic interactions, hydrogen bonding, and van der Waals forces. Additionally, we discuss the future prospects of this field. [Display omitted] • Interaction of ionic liquids with cellular membrane is favourable due to enhanced system entropy and reduced free energy. • Ionic liquids perturb the self-assembly of lipids in a cellular membrane. • Ionic liquids modify the mechano-elasticity of a cellular membrane. • Dynamics of lipids in a membrane at the presence of ionic liquids are altered. [ABSTRACT FROM AUTHOR]

The lipid matrix of cellular membranes is an elastic liquid crystalline medium. Its deformations regulate the functionality and interactions of membrane proteins,f membrane-bound peptides, lipid and protein-lipid domains. Gramicidin A (gA) is a peptide, which incorporates into membrane leaflets as a monomer and may form a transmembrane dimer. In both configurations, gA deforms the membrane. The transmembrane dimer of gA is a cation-selective ion channel. Its electrical response strongly depends on the elastic properties of the membrane. The gA monomer and dimer deform the membrane differently; therefore, the elastic energy contributes to the activation barriers of the dimerization and dissociation of the conducting state. It is shown experimentally that channel characteristics alter if gA molecules have been located in the vicinity of the conducting dimer. Here, based on the theory of elasticity of lipid membranes, we developed a quantitative theoretical model which allows explaining experimentally observed phenomena under conditions of high surface density of gA or its analogues, i.e., in the regime of strong lateral interactions of gA molecules, mediated by elastic deformations of the membrane. The model would be useful for the analysis and prediction of the gA electrical response in various experimental conditions. This potentially widens the possible applications of gA as a convenient molecular sensor of membrane elasticity.

β -aescin is a versatile biosurfactant extracted from the seeds of the horse chestnut tree Aesculus hippocastanum with anti-cancer potential and is commonly used in the food and pharmaceutical and cosmetic industries. In this article, wide-angle X-ray scattering (WAXS) is used in order to study the modifications of the structural parameters at the molecular scale of lipid bilayers in the form of bicelles composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and the triterpenoid saponin β -aescin. In particular, the impact on the cooperative phase transition and the structural parameters of the DMPC bilayers at different compositions and temperatures is of special interest. Moreover, we show how cholesterol and the non-steroidal anti-inflammatory drug (NSAID) ibuprofen modulate the structural parameters of the β -aescin-DMPC assemblies on a molecular scale. Ibuprofen and cholesterol interact with different parts of the bilayer, namely the head-region in the former and the tail-region in the latter case allowing for specific molecular packing and phase formation in the binary and ternary mixtures.

Bio-macromolecules as DNA, lipid membranes and (poly)peptides are essential compounds at the core of biological systems. The development of techniques and methodologies for their characterization is therefore necessary and of utmost interest, even though difficulties can be experienced due to their intrinsic complex nature. Among these methods, spectroscopies, relying on optical properties are especially important to determine their macromolecular structures and behaviors, as well as the possible interactions and reactivity with external dyes—often drugs or pollutants—that can (photo)sensitize the bio-macromolecule leading to eventual chemical modifications, thus damages. In this review, we will focus on the theoretical simulation of electronic spectroscopies of bio-macromolecules, considering their secondary structure and including their interaction with different kind of (photo)sensitizers. Namely, absorption, emission and electronic circular dichroism (CD) spectra are calculated and compared with the available experimental data. Non-linear properties will be also taken into account by two-photon absorption, a highly promising technique (i) to enhance absorption in the red and infra-red windows and (ii) to enhance spatial resolution. Methodologically, the implications of using implicit and explicit solvent, coupled to quantum and thermal samplings of the phase space, will be addressed. Especially, hybrid quantum mechanics/molecular mechanics (QM/MM) methods are explored for a comparison with solely QM methods, in order to address the necessity to consider an accurate description of environmental effects on spectroscopic properties of biological systems.

Our understanding of the electrical properties of cell membranes is derived from experiments where the membrane is exposed to a perturbation (in the form of a time-dependent voltage or current change) and information is extracted from the measured output. The interpretation of such electrical recordings consists in finding an electronic equivalent that would show the same or similar response as the biological system. In general, however, there is no unique circuit configuration, which can explain a single electrical recording and the choice of an electric model for a biological system is based on complementary information (most commonly structural information) of the system investigated. Most of the electrophysiological data on cell membranes address the functional role of protein channels while assuming that the lipid matrix is an insulator with constant capacitance. However, close to their melting transition the lipid bilayers are no inert insulators. Their conductivity and their capacitance are nonlinear functions of both voltage, area and volume density. This has to be considered when interpreting electrical data. Here we show how electric data commonly interpreted as gating currents of proteins and inductance can be explained by the nonlinear dynamics of the lipid matrix itself.