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The intrinsic pathway of apoptosis is regulated by the Bcl-2 family of proteins. Inhibition of the anti-apoptotic members represents a strategy to induce apoptotic cell death in cancer cells. We have measured the membrane binding properties of a series of peptides, including modified α/β-peptides, designed to exhibit enhanced membrane permeability to allow cell entry and improved access for engagement of Bcl-2 family members. The peptide cargo is based on the pro-apoptotic protein Bim, which interacts with all anti-apoptotic proteins to initiate apoptosis. The α/β-peptides contained cyclic β-amino acid residues designed to increase their stability and membrane permeability. Dual polarisation interferometry was used to study the binding of each peptide to two different model membrane systems designed to mimic either the plasma membrane or the outer mitochondrial membrane. The impact of each peptide on the model membrane structure was also investigated, and the results demonstrated that the modified peptides had increased affinity for the mitochondrial membrane and significantly altered the structure of the bilayer. The results also showed that the presence of an RRR motif significantly enhanced the ability of the peptides to bind to and insert into the mitochondrial membrane mimic, and provide insights into the role of selective membrane targeting of peptides. The membrane binding of two peptides designed to exhibit enhanced membrane permeability to allow cell entry and engagement of Bcl-2 family members shows that an RRR motif significantly enhances peptide binding and insertion into a mitochondrial membrane mimic and provides insights into selective membrane targeting of peptides. [ABSTRACT FROM AUTHOR]

Oxygen on its transport route from lung to tissue mitochondria has to cross several cell membranes. The permeability value of membranes for O2 (PO2), although of fundamental importance, is controversial. Previous studies by mostly indirect methods diverge between 0.6 and 125 cm/s. Here, we use a most direct approach by observing transmembrane O2 fluxes out of 100 nm liposomes at defined transmembrane O2 gradients in a stopped-flow system. Due to the small size of the liposomes intra- as well as extraliposomal diffusion processes do not affect the overall kinetics of the O2 release process. We find, for cholesterol-free liposomes, the unexpectedly low PO2 value of 0.03 cm/s at 35 °C. This PO2 would present a serious obstacle to O2 entering or leaving the erythrocyte. Cholesterol turns out to be a novel major modifier of PO2, able to increase PO2 by an order of magnitude. With a membrane cholesterol of 45 mol% as it occurs in erythrocytes, PO2 rises to 0.2 cm/s at 35 °C. This PO2 is just sufficient to ensure complete O2 loading during passage of erythrocytes through the lung's capillary bed under the conditions of rest as well as maximal exercise. [ABSTRACT FROM AUTHOR]

Transwell experiments with Caco-2 or MDCK cells are the gold standard for determining the intestinal permeability of chemicals. The intrinsic membrane permeability (P 0), that can be extracted from these experiments, might be comparable to P 0 measured in black lipid membrane (BLM) experiments and P 0 predicted by the solubility-diffusion model. Unfortunately, the overlap between experimental P 0,Caco-2/MDCK and P 0,BLM data is very small. So far, differences between both approaches have been attributed to the cholesterol and sphingomyelin content of cell membranes, but the database is too sparse to thoroughly test this theory. To create a diverse dataset, we measured P 0,BLM of ten chemicals in BLM experiments using DPhPC and DPhPC/cholesterol/sphingomyelin membranes. The results were compared to predicted BLM data and experimental Caco-2/MDCK data obtained from literature. While P 0,BLM of all chemicals was well predicted by the solubility-diffusion model, P 0,Caco-2/MDCK was only predictable for rather hydrophilic compounds with logarithmic hexadecane/water partition coefficients below −0.5. The effect of cholesterol and sphingomyelin on P 0,BLM was negligibly small. [Display omitted] • Cholesterol and sphingomyelin have no impact on the permeability of DPhPC membranes. • DPhPC membrane permeability is well predicted by the solubility-diffusion model. • Caco-2 permeability of lipophilic compounds differs from solubility-diffusion model. • DPhPC membranes can be used to predict Caco-2 permeability of hydrophilic compounds. [ABSTRACT FROM AUTHOR]

Quercetin is a polyphenolic molecule with a broad spectrum of biological activities derived from its antioxidant property. Its mechanism of action has been explained by its binding and/or interference with enzymes, receptors, transporters and signal transduction systems. Since these important mechanisms generally occur in membrane environments, within and through lipid bilayers, investigating the biophysical properties related to the diversity of lipid compositions of cell membranes may be the key to understanding the role of cell membrane in these processes. In this work, we explored the interaction of quercetin with model membranes of different lipid compositions to access the importance of lipid phases and bilayer homogeneity to the action of quercetin and contribute to the understanding of quercetin multiple activities. Analysis of the influence of quercetin on the morphology and permeability of GUVs, the rigidity of LUVs and affinity to these vesicles showed that quercetin strongly partitions to the more homogeneous environments, but significantly permeates and modifies the more heterogeneous where liquid-disordered, liquid-ordered and solid phases coexist. Our findings support the condensing effect of quercetin, which is observed through a significant rigidifying of bilayers containing 40% cholesterol, but much less evidenced when it is reduced to 20% or in its absence. Nevertheless, the presence of sphingomyelin in the ternary system led to a more heterogeneous bilayer with the formation of micrometric and probably also nanometric domains, which coalesce in the presence of quercetin. This observation together with increased permeability points to an insertion effect. [Display omitted] • Quercetin significantly increases membrane permeability depending on the presence of micrometric lipid domains. • Quercetin rigidifies bilayers, exerting a condensation effect which is cholesterol-content dependent. • Quercetin strongly partitions to the more homogeneous lipid bilayers with a preference for those of higher ld fractions. • Quercetin induces the coalescence of micrometric domains in vesicles containing sphingomyelin. • Lipid domains coalescence and increased permeability point to quercetin interdigitation effect in ternary bilayer. [ABSTRACT FROM AUTHOR]

Human cell membranes consist of various lipids that are essential for their structure and function. It typically comprises phosphatidylcholine (POPC), phosphatidylethanolamine (POPE), phosphatidylserine (POPS), sphingomyelin (PSM), and cholesterol (CHL). Several experimental and computational techniques have been employed to characterize the composition of human cell membranes, however, CHL enriched membrane is still not clearly understood through these techniques. Molecular dynamics simulation results illustrated the biophysical properties of heterogeneous membranes based on the lipid composition as well as the concentration of lipids, exclusively for CHL and PSM. Herein, we have investigated the structure-function relationships of lipids comparatively to delineate the effect of heterogeneity on the biophysical properties of different membranes. It has been observed that the significant fraction of CHL (i.e., ~33% in ternary, ~25% in quaternary, and ~16% in senary type bilayers) in combination with other lipids introduced compactness, and increased the thickness of the membrane. The analysis of lipid mass density stated that the density of lipid head group, phosphate , and glycerol-ester in presence of CHL with or without PSM is an underlying reason for membrane ordering. Results also revealed that the presence of POPI and POPS are the reasons for an adequate drop in the ordering of lipid chain, particularly on POPE chain. The self-interaction of CHL, PSM, POPE and the interaction of CHL and POPC with POPE seem to determine the structure and function of the heterogeneous membrane. Our findings provide a qualitative understanding of the effect of membrane heterogeneity on the physiological properties of membranes. The structures inspected in this study would help to select the heterogeneous bilayer model to mimic the human cell membranes to analyse or characterize the membrane-associated phenomena. [Display omitted] • Structure-function relationship of lipids to delineate the effect of heterogeneity on the biophysical properties of membranes. • The membrane ordering depends on the density of lipid head group, phosphate, and glycerol-ester in presence of CHL with or without PSM. • Results also revealed the POPI and POPS are the reasons for an adequate drop in the ordering of lipid chain particularly of POPE chain. [ABSTRACT FROM AUTHOR]

[Display omitted] The formation of transient pores in their membranes is a well-known mechanism of permeabilization of cells exposed to high-intensity electric pulses. However, the formation of such pores is not able to explain all aspects of the so-called electroporation phenomenon. In particular, the reasons for sustained permeability of cell membranes, persisting long after the pulses' application, remain elusive. The complete resealing of cell membranes takes indeed orders of magnitude longer than the time for electropore closure as reported from molecular dynamics (MD) investigations. Lipid peroxidation has been suggested as a possible mechanism to explain the sustainable permeability of cell membranes. However, theoretical investigations of membrane lesions containing excess amounts of hydroperoxides have shown that the conductivities of such lesions were not high enough to account for the experimental measurements. Here, expanding on these studies, we investigate quantitatively the permeability of cell membrane lesions that underwent secondary oxidation. MD simulations and free energy calculations of lipid bilayers show that such lesions provide a better model of post-pulse permeable and conductive electropermeabilized cells. These results are further discussed in the context of sonoporation and ferroptosis, respectively a procedure and a phenomenon, among others, in which, alike electroporation, substantial lipid oxidation might be triggered. [ABSTRACT FROM AUTHOR]

Drug-membrane interactions immediately occur when drugs are administered, independently of the route of administration or the target location (i.e., intracellular or within the membrane) [[1]]. In this Special Issue entitled " I Study on Drug-Membrane Interactions" i , several elegant contributions on drug-membrane interaction studies field were provided. Different biophysical methods can be used to understand drug-membrane interactions and gain better knowledge about the drugs' pharmacokinetic, pharmacodynamic and toxicity, and consequently, potential side effects of drugs [[1]]. [Extracted from the article]