Query: membrane permeability

title: Maximizing the right stuff: The trade off between membrane permeability and selectivity
abstract: Filtering through to what's important Membranes are widely used for gas and liquid separations. Historical analysis of a range of gas pair separations indicated that there was an upper bound on the trade off between membrane permeability, which limits flow rates, and the selectivity, which limits the quality of the separation process. Park et al. review the advances that have been made in attempts to break past this upper bound. Some inspiration has come from biological membranes. The authors also highlight cases where the challenges lie in areas other than improved separation performance. Science, this issue p.  BACKGROUND Synthetic membranes are used for desalination, dialysis, sterile filtration, food processing, dehydration of air and other industrial, medical, and environmental applications due to low energy requirements, compact design, and mechanical simplicity. New applications are emerging from the water energy nexus, shale gas extraction, and environmental needs such as carbon capture. All membranes exhibit a trade off between permeability i.e. how fast molecules pass through a membrane material and selectivity i.e. to what extent the desired molecules are separated from the rest. However, biological membranes such as aquaporins and ion channels are both highly permeable and highly selective. Separation based on size difference is common, but there are other ways to either block one component or enhance transport of another through a membrane. Based on increasing molecular understanding of both biological and synthetic membranes, key design criteria for new membranes have emerged: (i) properly sized free volume elements (or pores) (ii) narrow free volume element (or pore size) distribution, (iii) a thin active layer, and (iv) highly tuned interactions between permeants of interest and the membrane. Here, we discuss the permeability/selectivity trade off, highlight similarities and differences between synthetic and biological membranes, describe challenges for existing membranes, and identify fruitful areas of future research.  Many organic, inorganic, and hybrid materials have emerged as potential membranes. In addition to polymers, used for most membranes today, materials such as carbon molecular sieves, ceramics, zeolites, various nanomaterials (e.g. graphene, graphene oxide, and metal organic frameworks) and their mixtures with polymers have been explored. Simultaneously, global challenges such as climate change and rapid population growth stimulate the search for efficient water purification and energy generation technologies, many of which are membrane based. Additional driving forces include wastewater reuse from shale gas extraction and improvement of chemical and petrochemical separation processes by increasing the use of light hydrocarbons for chemicals manufacturing. OUTLOOK Opportunities for advancing membranes include (i) more mechanically, chemically, and thermally robust materials; (ii) judiciously higher permeability and selectivity for applications where such improvements matter; and (iii) more emphasis on fundamental structure/property/processing relations. There is a pressing need for membranes with improved selectivity, rather than membranes with improved permeability, especially for water purification. Modeling at all length scales is needed to develop a coherent molecular understanding of membrane properties, provide insight for future materials design, and clarify the fundamental basis for trade off behavior. Basic molecular level understanding of thermodynamic and diffusion properties of water and ions in charged membranes for desalination and energy applications such as fuel cells is largely incomplete. Fundamental understanding of membrane structure optimization to control transport of minor species (e.g. trace organic contaminants in desalination membranes, neutral compounds in charged membranes, and heavy hydrocarbons in membranes for natural gas separation) is needed. Laboratory evaluation of membranes is often conducted with highly idealized mixtures, so separation performance in real applications with complex mixtures is poorly understood. Lack of systematic understanding of methodologies to scale promising membranes from the few square centimeters needed for laboratory studies to the thousands of square meters needed for large applications stymies membrane deployment. Nevertheless, opportunities for membranes in both existing and emerging applications, together with an expanding set of membrane materials, hold great promise for membranes to effectively address separations needs. From intrinsic permeability/selectivity trade off to practical performance in membranes. Polymer membranes for liquid and gas separation applications obey a permeability/selectivity trade off highly permeable membranes have low selectivity and vice versa largely due to broad distributions of free volume elements (or pores in porous membranes) and nonspecific interactions between small solutes and polymers. We highlight materials approaches to overcome this trade off, including the development of inorganic, isoporous, mixed matrix, and aquaporin membranes. Further, materials must be processed into thin, typically supported membranes, fashioned into high surface/volume ratio modules, and used in optimized processes. Thus, factors that govern the practical feasibility of membranes such as mechanical strength, module design, and operating conditions are also discussed. Increasing demands for energy efficient separations in applications ranging from water purification to petroleum refining, chemicals production, and carbon capture have stimulated a vigorous search for novel, high performance separation membranes. Synthetic membranes suffer a ubiquitous, pernicious trade off: highly permeable membranes lack selectivity and vice versa. However, materials with both high permeability and high selectivity are beginning to emerge. For example, design features from biological membranes have been applied to break the permeability selectivity trade off. We review the basis for the permeability selectivity trade off, state of the art approaches to membrane materials design to overcome the trade off, and factors other than permeability and selectivity that govern membrane performance and, in turn, influence membrane design.

title: Understanding antibiotic resistance via outer membrane permeability
abstract: Collective antibiotic drug resistance is a global threat, especially with respect to Gram negative bacteria. The low permeability of the bacterial outer cell wall has been identified as a challenging barrier that prevents a sufficient antibiotic effect to be attained at low doses of the antibiotic. The Gram negative bacterial cell envelope comprises an outer membrane that delimits the periplasm from the exterior milieu. The crucial mechanisms of antibiotic entry via outer membrane includes general diffusion porins (Omps) responsible for hydrophilic antibiotics and lipid mediated pathway for hydrophobic antibiotics. The protein and lipid arrangements of the outer membrane have had a strong impact on the understanding of bacteria and their resistance to many types of antibiotics. Thus, one of the current challenges is effective interpretation at the molecular basis of the outer membrane permeability. This review attempts to develop a state of knowledge pertinent to Omps and their effective role in solute influx. Moreover, it aims toward further understanding and exploration of prospects to improve our knowledge of physicochemical limitations that direct the translocation of antibiotics via bacterial outer membrane.

title: Predicting a Drug's Membrane Permeability: A Computational Model Validated With in Vitro Permeability Assay Data.
abstract: Membrane permeability is a key property to consider during the drug design process, and particularly vital when dealing with small molecules that have intracellular targets as their efficacy highly depends on their ability to cross the membrane. In this work, we describe the use of umbrella sampling molecular dynamics (MD) computational modeling to comprehensively assess the passive permeability profile of a range of compounds through a lipid bilayer. The model was initially calibrated through in vitro validation studies employing a parallel artificial membrane permeability assay (PAMPA) The model was subsequently evaluated for its quantitative prediction of permeability profiles for a series of custom synthesized and closely related compounds. The results exhibited substantially improved agreement with the PAMPA data, relative to alternative existing methods. Our work introduces a computational model that underwent progressive molding and fine tuning as a result of its synergistic collaboration with numerous in vitro PAMPA permeability assays. The presented computational model introduces itself as a useful, predictive tool for permeability prediction.

title: Simulation Based Approaches for Determining Membrane Permeability of Small Compounds
abstract: Predicting the rate of nonfacilitated permeation of solutes across lipid bilayers is important to drug design, toxicology, and signaling. These rates can be estimated using molecular dynamics simulations combined with the inhomogeneous solubility diffusion model, which requires calculation of the potential of mean force and position dependent diffusivity of the solute along the transmembrane axis. In this paper, we assess the efficiency and accuracy of several methods for the calculation of the permeability of a model DMPC bilayer to urea, benzoic acid, and codeine. We compare umbrella sampling, replica exchange umbrella sampling, adaptive biasing force, and multiple walker adaptive biasing force for the calculation of the transmembrane PMF. No definitive advantage for any of these methods in their ability to predict the membrane permeability coefficient Pm was found, provided that a sufficiently long equilibration is performed. For diffusivities, a Bayesian inference method was compared to a generalized Langevin method, both being sensitive to chosen parameters and the slow relaxation of membrane defects. Agreement within 1.5 log units of the computed Pm with experiment is found for all permeants and methods. Remaining discrepancies can likely be attributed to limitations of the force field as well as slowly relaxing collective movements within the lipid environment. Numerical calculations based on model profiles show that Pm can be reliably estimated from only a few data points, leading to recommendations for calculating Pm from simulations.

title: Autophagic cell death is dependent on lysosomal membrane permeability through Bax and Bak
abstract: Cells deficient in the pro death Bcl 2 family members Bax and Bak are known to be resistant to apoptotic cell death, and previous we have shown that these two effectors are also needed for mitochondrial dependent cellular necrosis (Karch et al. 2013) Here we show that mouse embryonic fibroblasts deficient in Bax/Bak1 are resistant to the third major form of cell death associated with autophagy through a mechanism involving lysosome permeability. Indeed, specifically targeting Bax only to the lysosome restores autophagic cell death in Bax/Bak1 null cells. Moreover, a monomeric only mutant form of Bax is sufficient to increase lysosomal membrane permeability and restore autophagic cell death in Bax/Bak1 double deleted mouse embryonic fibroblasts. Finally, increasing lysosomal permeability through a lysomotropic detergent in cells devoid of Bax/Bak1 restores autophagic cell death, collectively indicting that Bax/Bak integrate all major forms of cell death through direct effects on membrane permeability of multiple intracellular organelles.

title: Molecular Basis of Bacterial Outer Membrane Permeability Revisited
abstract: Gram negative bacteria characteristically are surrounded by an additional membrane layer, the outer membrane. Although outer membrane components often play important roles in the interaction of symbiotic or pathogenic bacteria with their host organisms, the major role of this membrane must usually be to serve as a permeability barrier to prevent the entry of noxious compounds and at the same time to allow the influx of nutrient molecules. This review summarizes the development in the field since our previous review (H. Nikaido and M. Vaara, Microbiol. Rev. 49:1 32, 1985) was published. With the discovery of protein channels, structural knowledge enables us to understand in molecular detail how porins, specific channels, TonB linked receptors, and other proteins function. We are now beginning to see how the export of large proteins occurs across the outer membrane. With our knowledge of the lipopolysaccharide phospholipid asymmetric bilayer of the outer membrane, we are finally beginning to understand how this bilayer can retard the entry of lipophilic compounds, owing to our increasing knowledge about the chemistry of lipopolysaccharide from diverse organisms and the way in which lipopolysaccharide structure is modified by environmental conditions.

title: Phenylalanine Increases Membrane Permeability.
abstract: Biological membranes are a crucial aspect of living systems, controlling the organization and distribution of different chemical components. Control of membrane permeability is especially important for processes such as electron transport in metabolism and signal propagation in nerve cells. In this work, we show that the amino acid phenylalanine produces increased membrane permeability, which is likely responsible for some of the deleterious symptoms associated with high biological phenylalanine concentrations that occur with the genetic disorder phenylketonuria.

title: Improving the Membrane Permeability of 5 Fluorouracil via Cocrystallization
abstract: Pharmaceutical cocrystallization is proposed as a new method to enhance membrane permeability of a BCS class III model drug, 5 fluorouracil (5FU) Three cocrystals of 5FU, 5FU/3 hydroxybenzoic acid (1) 5FU/4 aminobenzoic acid (2) and 5FU/cinnamic acid (3) were successfully synthesized by a slurry method or a liquid assisted grinding process. Spectroscopic methods, thermal analysis, and X ray diffraction were used to characterize these new forms. The permeability was studied using a Franz diffusion cell and silicone membrane. All of the cocrystals showed improved membrane permeability compared to free 5FU. The cumulative amount per unit area of permeated 5FU in the first 10 h for 1 3 was increased by 41, 70, and 83% and the steady penetration rates of 1 3 were increased by 38, 66, and 79% respectively, as compared to the pure drug. Structure permeability correlation study finds a link between intermolecular interactions and molecular packing in cocrystals and their permeability behavior and has import.

title: Alteration of Zeta potential and membrane permeability in bacteria: a study with cationic agents
abstract: In the present study, we have tried to establish the correlation between changes in Zeta potential with that of cell surface permeability using bacteria (Escherichia coli and Staphylococcus aureus) An effort has been made to establish Zeta potential as a possible marker for the assessment of membrane damage, with a scope for predicting alteration of cell viability. Cationic agents like, cetyl trimethyl ammonium bromide and polymyxin B were used for inducing alteration of Zeta potential, and the changes occurring in the membrane permeability were studied. In addition, assessment of poly dispersity index (PDI) cell viability along with confocal microscopic analysis were performed. Based on our results, it can be suggested that alteration of Zeta potential may be correlated to the enhancement of membrane permeability and PDI, and it was observed that beyond a critical point, it leads to cell death (both Gram positive and Gram negative bacteria) The present findings can not only be used for studying membrane active molecules but also for understanding the surface potential versus permeability relationship.

title: High Membrane Permeability for Melatonin
abstract: The pineal gland is the endocrine organ in the brain that synthesizes and secretes the circulating night hormone melatonin throughout the night. How is this hormone secreted? Is it by calcium dependent vesicular exocytosis or by simple diffusion across the pinealocyte plasma membrane? Experiments were designed to compare the cell membrane permeability to three indoleamines: melatonin and its precursors N acetyl serotonin (NAS) and serotonin. The three experimental approaches were (i) to measure the concentration of indoleamine amperometrically in the bath while cells were being loaded by a whole cell pipette, (ii) to measure the rise of intracellular indoleamine fluorescence as the compound was perfused in the bath, and (iii) to measure the rate of quenching of intracellular fura 2 dye fluorescence as indoleamines were perfused extracellularly in the bath. These measures showed that permeabilities of melatonin and NAS are high (both are uncharged) whereas that for serotonin (mostly charged) is much lower: melatonin NAS serotonin. Comparisons are made with predictions of solubility diffusion theory and compounds of known permeability, and a diffusion model is made to simulate all the measurements. The bottom line is that melatonin equilibrates across the plasma membrane in 3.5 s and has a membrane permeability of ~1.7 mm/s. Thus it and NAS will be "secreted" from pineal cells by membrane diffusion within seconds of synthesis. Circumstances are suggested when serotonin and possibly catecholamines (mostly charged) may also appear in the extracellular space passively by membrane diffusion from processes with high surface to volume ratio.Supported by National Institutes of Health grants R01GM 83913, R37NS 008174 and R01DK 080840.