Assessing vitamin E acetate as a proxy for E-cigarette additives in a realistic pulmonary surfactant model.

Additives in vaping products, such as flavors, preservatives, or thickening agents, are commonly used to enhance user experience. Among these, Vitamin E acetate (VEA) was initially thought to be harmless but has been implicated as the primary cause of e-cigarette or vaping product use-associated lung injury, a serious lung disease. In our study, VEA serves as a proxy for other e-cigarette additives.

Adipogenin Dictates Adipose Tissue Expansion by Facilitating the Assembly of a Dodecameric Seipin Complex.

Adipogenin (Adig) is an evolutionarily conserved microprotein and is highly expressed in adipose tissues and testis. Here, we identify Adig as a critical regulator for lipid droplet formation in adipocytes. We determine that Adig interacts directly with seipin, leading to the formation of a rigid complex.

Insights into short chain polyethylene penetration of phospholipid bilayers via atomistic molecular dynamics simulations.

The escalation of global plastic production, reaching an annual output of 400 million tons, has significantly intensified concerns regarding plastic waste management. This has been exacerbated by improper recycling and disposal practices, contributing to the impending crisis of plastic pollution. Predictions indicate that by 2025, the environment will bear the burden of over ten billion metric tons of accumulated plastic waste.

Revealing the key structural features promoting the helical conformation in algal polysaccharide carrageenan in solution.

Carrageenans are industrially important polysaccharides with tunable viscoelastic and gelation properties. The function of polysaccharide depends on its conformation and chemical composition. However, the solution conformations of carrageenans are highly debated, and the structure-function relationship remains elusive.

Deciphering Lipid Arrangement in Phosphatidylserine/Phosphatidylcholine Mixed Membranes: Simulations and Experiments.

Phosphatidylserine (PS) exposure on the plasma membrane is crucial for many cellular processes including apoptotic cell recognition, blood clotting regulation, cellular signaling, and intercellular interactions. In this study, we investigated the arrangement of PS headgroups in mixed PS/phosphatidylcholine (PC) bilayers, serving as a simplified model of the outer leaflets of mammalian cell plasma membranes. Combining atomistic-scale molecular dynamics (MD) simulations with Langmuir monolayer experiments, we unraveled the mutual miscibility of POPC and POPS lipids and the intricate intermolecular interactions inherent to these membranes as well as the disparities in position and orientation of PC and PS headgroups.

In Vitro and In Silico Studies of Functionalized Polyurethane Surfaces toward Understanding Biologically Relevant Interactions.

The solid-aqueous boundary formed upon biomaterial implantation provides a playground for most biochemical reactions and physiological processes involved in implant-host interactions. Therefore, for biomaterial development, optimization, and application, it is essential to understand the biomaterial-water interface in depth. In this study, oxygen plasma-functionalized polyurethane surfaces that can be successfully utilized in contact with the tissue of the respiratory system were prepared and investigated.

How Neuromembrane Lipids Modulate Membrane Proteins: Insights from G-Protein-Coupled Receptors (GPCRs) and Receptor Tyrosine Kinases (RTKs).

Lipids play a diverse and critical role in cellular processes in all tissues. The unique lipid composition of nerve membranes is particularly interesting because it contains, among other things, polyunsaturated lipids, such as docosahexaenoic acid, which the body only gets through the diet. The crucial role of lipids in neurological processes, especially in receptor-mediated cell signaling, is emphasized by the fact that in many neuropathological diseases there are significant deviations in the lipid composition of nerve membranes compared to healthy individuals.

Miscibility of Phosphatidylcholines in Bilayers: Effect of Acyl Chain Unsaturation.

The miscibility of phospholipids in a hydrated bilayer is an issue of fundamental importance for understanding the organization of biological membranes. Despite research on lipid miscibility, its molecular basis remains poorly understood. In this study, all-atom MD simulations complemented by Langmuir monolayer and DSC experiments have been performed to investigate the molecular organization and properties of lipid bilayers composed of phosphatidylcholines with saturated (palmitoyl, DPPC) and unsaturated (oleoyl, DOPC) acyl chains.

Dissecting the mechanisms of environment sensitivity of smart probes for quantitative assessment of membrane properties.

The plasma membrane, as a highly complex cell organelle, serves as a crucial platform for a multitude of cellular processes. Its collective biophysical properties are largely determined by the structural diversity of the different lipid species it accommodates. Therefore, a detailed investigation of biophysical properties of the plasma membrane is of utmost importance for a comprehensive understanding of biological processes occurring therein.

Maturation of the SARS-CoV-2 virus is regulated by dimerization of its main protease.

SARS-CoV-2 main protease (M) involved in COVID-19 is required for maturation of the virus and infection of host cells. The key question is how to block the activity of M. By combining atomistic simulations with machine learning, we found that the enzyme regulates its own activity by a collective allosteric mechanism that involves dimerization and binding of a single substrate.

A cholesterol analog stabilizes the human β-adrenergic receptor nonlinearly with temperature.

In cell membranes, G protein-coupled receptors (GPCRs) interact with cholesterol, which modulates their assembly, stability, and conformation. Previous studies have shown how cholesterol modulates the structural properties of GPCRs at ambient temperature. Here, we characterized the mechanical, kinetic, and energetic properties of the human β-adrenergic receptor (βAR) in the presence and absence of the cholesterol analog cholesteryl hemisuccinate (CHS) at room temperature (25°C), at physiological temperature (37°C), and at high temperature (42°C).

Dimerization of the pulmonary surfactant protein C in a membrane environment.

Surfactant protein C (SP-C) has several functions in pulmonary surfactant. These include the transfer of lipids between different membrane structures, a role in surfactant recycling and homeostasis, and involvement in modulation of the innate defense system. Despite these important functions, the structures of functional SP-C complexes have remained unclear.

Mcl-1 and Bok transmembrane domains: Unexpected players in the modulation of apoptosis.

The Bcl-2 protein family comprises both pro- and antiapoptotic members that control the permeabilization of the mitochondrial outer membrane, a crucial step in the modulation of apoptosis. Recent research has demonstrated that the carboxyl-terminal transmembrane domain (TMD) of some Bcl-2 protein family members can modulate apoptosis; however, the transmembrane interactome of the antiapoptotic protein Mcl-1 remains largely unexplored. Here, we demonstrate that the Mcl-1 TMD forms homooligomers in the mitochondrial membrane, competes with full-length Mcl-1 protein with regards to its antiapoptotic function, and induces cell death in a Bok-dependent manner.

Rigorous Computational Study Reveals What Docking Overlooks: Double Trouble from Membrane Association in Protein Kinase C Modulators.

Increasing protein kinase C (PKC) activity is of potential therapeutic value. Its activation involves an interaction between the C1 domain and diacylglycerol (DAG) at intracellular membrane surfaces; DAG mimetics hold promise as new drugs. We previously developed the isophthalate derivative HMI-1a3, an effective but highly lipophilic (clog = 6.

Tail-Oxidized Cholesterol Enhances Membrane Permeability for Small Solutes.

Cholesterol renders mammalian cell membranes more compact by reducing the amount of voids in the membrane structure. Because of this, cholesterol is known to regulate the ability of cell membranes to prevent the permeation of water and water-soluble molecules through the membranes. Meanwhile, it is also known that even seemingly tiny modifications in the chemical structure of cholesterol can lead to notable changes in membrane properties.

Functionalization of the Parylene C Surface Enhances the Nucleation of Calcium Phosphate: Combined Experimental and Molecular Dynamics Simulations Approach.

Interactions at the solid-body fluid interfaces play a vital role in bone tissue formation at the implant surface. In this study, fully atomistic molecular dynamics (MD) simulations were performed to investigate interactions between the physiological components of body fluids (Ca, HPO, HPO, Na, Cl, and HO) and functionalized parylene C surface. In comparison to the native parylene C (-Cl surface groups), the introduction of -OH, -CHO, and -COOH surface groups significantly enhances the interactions between body fluid ions and the polymeric surface.

Reduced level of docosahexaenoic acid shifts GPCR neuroreceptors to less ordered membrane regions.

G protein-coupled receptors (GPCRs) control cellular signaling and responses. Many of these GPCRs are modulated by cholesterol and polyunsaturated fatty acids (PUFAs) which have been shown to co-exist with saturated lipids in ordered membrane domains. However, the lipid compositions of such domains extracted from the brain cortex tissue of individuals suffering from GPCR-associated neurological disorders show drastically lowered levels of PUFAs.

Complex Behavior of Phosphatidylcholine-Phosphatidic Acid Bilayers and Monolayers: Effect of Acyl Chain Unsaturation.

Phosphatidic acids (PAs) have many biological functions in biomembranes, e.g., they are involved in the proliferation, differentiation, and transformation of cells.

Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance.

Biological membranes are tricky to investigate. They are complex in terms of molecular composition and structure, functional over a wide range of time scales, and characterized by nonequilibrium conditions. Because of all of these features, simulations are a great technique to study biomembrane behavior.

How to minimize dye-induced perturbations while studying biomembrane structure and dynamics: PEG linkers as a rational alternative.

Organic dye-tagged lipid analogs are essential for many fluorescence-based investigations of complex membrane structures, especially when using advanced microscopy approaches. However, lipid analogs may interfere with membrane structure and dynamics, and it is not obvious that the properties of lipid analogs would match those of non-labeled host lipids. In this work, we bridged atomistic simulations with super-resolution imaging experiments and biomimetic membranes to assess the performance of commonly used sphingomyelin-based lipid analogs.

Physiologically-relevant levels of sphingomyelin, but not GM1, induces a β-sheet-rich structure in the amyloid-β(1-42) monomer.

To resolve the contribution of ceramide-containing lipids to the aggregation of the amyloid-β protein into β-sheet rich toxic oligomers, we employed molecular dynamics simulations to study the effect of cholesterol-containing bilayers comprised of POPC (70% POPC, and 30% cholesterol) and physiologically relevant concentrations of sphingomyelin (SM) (30% SM, 40% POPC, and 30% cholesterol), and the GM1 ganglioside (5% GM1, 70% POPC, and 25% cholesterol). The increased bilayer rigidity provided by SM (and to a lesser degree, GM1) reduced the interactions between the SM-enriched bilayer and the N-terminus of Aβ42 (and also residues Ser26, Asn27, and Lys28), which facilitated the formation of a β-sheet in the normally disordered N-terminal region. Aβ42 remained anchored to the SM-enriched bilayer through hydrogen bonds with the side chain of Arg5.

Cholesterol Protects the Oxidized Lipid Bilayer from Water Injury: An All-Atom Molecular Dynamics Study.

In an effort to delineate how cholesterol protects membrane structure under oxidative stress conditions, we monitored the changes to the structure of lipid bilayers comprising 30 mol% cholesterol and an increasing concentration of Class B oxidized 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) glycerophospholipids, namely, 1-palmitoyl-2-(9'-oxo-nonanoyl)-sn-glycero-3-phosphocholine (PoxnoPC), and 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PazePC), using atomistic molecular dynamics simulations. Increasing the content of oxidized phospholipids (oxPLs) from 0 to 60 mol% oxPL resulted in a characteristic reduction in bilayer thickness and increase in area per lipid, thereby increasing the exposure of the membrane hydrophobic region to water. However, cholesterol was observed to help reduce water injury by moving into the bilayer core and forming more hydrogen bonds with the oxPLs.

Bobbing of Oxysterols: Molecular Mechanism for Translocation of Tail-Oxidized Sterols through Biological Membranes.

Translocation of sterols between cellular membrane leaflets is of key importance in membrane organization, dynamics, and signaling. We present a novel translocation mechanism that differs in a unique manner from the established ones. The bobbing mechanism identified here is demonstrated for tail-oxidized sterols, but is expected to be viable for any molecule containing two polar centers at the opposite sides of the molecule.

The role of hydrophobic matching on transmembrane helix packing in cells.

Folding and packing of membrane proteins are highly influenced by the lipidic component of the membrane. Here, we explore how the hydrophobic mismatch (the difference between the hydrophobic span of a transmembrane protein region and the hydrophobic thickness of the lipid membrane around the protein) influences transmembrane helix packing in a cellular environment. Using a ToxRED assay in and a Bimolecular Fluorescent Complementation approach in human-derived cells complemented by atomistic molecular dynamics simulations we analyzed the dimerization of Glycophorin A derived transmembrane segments.