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We present super-resolution microscopy of isolated functional mitochondria, enabling real-time studies of structure and function (voltages) in response to pharmacological manipulation. Changes in mitochondrial membrane potential as a function of time and position can be imaged in different metabolic states (not possible in whole cells), created by the addition of substrates and inhibitors of the electron transport chain, enabled by the isolation of vital mitochondria. By careful analysis of structure dyes and voltage dyes (lipophilic cations), we demonstrate that most of the fluorescent signal seen from voltage dyes is due to membrane bound dyes, and develop a model for the membrane potential dependence of the fluorescence contrast for the case of super-resolution imaging, and how it relates to membrane potential. This permits direct analysis of mitochondrial structure and function (voltage) of isolated, individual mitochondria as well as submitochondrial structures in the functional, intact state, a major advance in super-resolution studies of living organelles.

[Display omitted] The interactions of viral fusion peptides from influenza (E4K and Ac-E4K) and human immunodeficiency virus (gp41 and Ac-gp41) with planar lipid bilayers and monolayers was investigated herein. A combination of surface-sensitive techniques, including quartz crystal microbalance with dissipation (QCM-D), Langmuir-Blodgett area-pressure isotherms with Micro-Brewster angle microscopy, and neutron reflectometry, was employed. Differences in the interactions of the viral fusion peptides with lipid bilayers featuring ordered and disordered phases, as well as lipid rafts, were revealed. The HIV fusion peptide (gp41) exhibited strong binding to the DOPC/DOPS bilayer, comprising a liquid disordered phase, with neutron reflectometry (NR) showing interaction with the bilayer's headgroup area. Conversely, negligible binding was observed with lipid bilayers in a liquid ordered phase. Notably, the influenza peptide (E4K) demonstrated slower binding kinetics with DOPC/DOPS bilayers and distinct interactions compared to gp41, as observed through QCM-D. This suggests different mechanisms of interaction with the lipid bilayers: one peptide interacts more within the headgroup region, while the other is more involved in transmembrane interactions. These findings hold implications for understanding viral fusion mechanisms and developing antimicrobials and antivirals targeting membrane interactions. The differential binding behaviours of the viral fusion peptides underscore the importance of considering membrane composition and properties in therapeutic strategy design. [ABSTRACT FROM AUTHOR]

Single‐walled carbon nanotubes (CNTs) are carbon materials with unique thermal, optical, mechanical, and electrical properties, with hollow cylindrical structures of a few nanometers in diameter. CNTs cut to about 10 nm (Ultrashort CNTs, US‐CNTs) can spontaneously insert into lipid bilayers. Therefore, applications have been proposed to combine CNTs with lipid bilayers to give the membranes the properties of CNTs. However, CNTs interact with membranes to induce morphological changes in the membranes, which may hinder these applications. In this study, to investigate the effects, US‐CNTs are exposed to lipid bilayer vesicles (giant unilamellar vesicles, GUVs), which are used as a model for cell membranes, and the changes in membrane morphology with each US‐CNT concentration were evaluated by fluorescence microscopy. As a result, GUVs show morphological changes upon exposure to US‐CNTs, eventually transforming into a multiple vesicle‐linked shape. This result suggests an increase in the area and asymmetry of the GUV membrane. Based on these results, we have proposed a hypothesis regarding the mechanism of morphological changes induced in the GUV membranes by US‐CNTs exposure. [ABSTRACT FROM AUTHOR]

In this work, we demonstrate that a functional modeling the self-aggregation of stochastically distributed lipid molecules can be obtained as the Γ -limit of a family of discrete energies driven by a sequence of independent and identically distributed random variables. These random variables are intended to describe the asymptotic behavior of lipid molecules that satisfy an incompressibility condition. The discrete energy keeps into account the interactions between particles. We resort to transportation maps to compare functionals defined on discrete and continuous domains, and we prove that, under suitable conditions on the scaling of these maps as the number of random variables increases, the limit functional features an interfacial term with a Wasserstein-type penalization. [ABSTRACT FROM AUTHOR]

Biohybrid membranes, combining a self-assembled lipid bilayer structure with functional nanomaterials/molecules, are promising candidates for ionic, optical, and electronic applications. However, information concerning the basic properties of these types of ultrathin hybrid membranes remains limited, primarily due to their low structural strength and low stability in air. In this work, we report on the successful formation of large-area ultrathin hybrid membranes composed of lipid and phthalocyanine molecules. The basic optical properties, mainly the light absorption and light emission properties, of the membranes were systematically investigated. The phthalocyanine molecules did not form an ordered crystal structure and were partially aggregated and dispersed in the hybrid membranes. Because the phthalocyanine molecules and the substrate were separated only by a monolayer of lipid molecules, the light-excited phthalocyanine molecules transferred the absorbed energy to the metal substrate, which led to the quenching of the emitted light. These unique properties of the hybrid membranes could be utilized in a variety of optoelectronic applications such as bioelectronic interfaces and photodetectors. [ABSTRACT FROM AUTHOR]

The widely used Laurdan probe has two conformers, resulting in different optical properties when embedded in a lipid bilayer membrane, as demonstrated by our previous simulations. Up to now, the two conformers' optical responses have, however, not been investigated when the temperature and the phase of the membrane change. Since Laurdan is known to be both a molecular rotor and a solvatochromic probe, it is subject to a profound interaction with both neighboring lipids and water molecules. In the current study, molecular dynamics simulations and hybrid Quantum Mechanics/Molecular Mechanics calculations are performed for a DPPC membrane at eight temperatures between 270K and 320K, while the position, orientation, fluorescence lifetime and fluorescence anisotropy of the embedded probes are monitored. The importance of both conformers is proven through a stringent comparison with experiments, which corroborates the theoretical findings. It is seen that for Conf-I, the excited state lifetime is longer than the relaxation of the environment, while for Conf-II, the surroundings are not yet adapted when the probe returns to the ground state. Throughout the temperature range, the lifetime and anisotropy decay curves can be used to identify the different membrane phases. The current work might, therefore, be of importance for biomedical studies on diseases, which are associated with cell membrane transformations. [ABSTRACT FROM AUTHOR]

Numerous non-cardiovascular drugs induce QT interval prolongations on electrocardiography and life-threatening torsades de pointes cardiac arrhythmias by blocking human ether-à-go-go- related gene (hERG) currents. The canonical binding sites for these small, basic compounds are located in the pore of the channel, accessible from the cytosolic side. Using cryoelectron microscopy, the molecular structures of both the hERG channel without ligand and the hERG channel in complex with a blocker (astemizole) have been recently determined. There are several putative noncanonical binding sites for hERG current blockers located outside the pore; that is, extracellular binding sites [especially the long extracellular loop between S5 and S6 (the 'turret')], intracellular binding sites at the channel entrance, hydrophobic pathways to plasma membrane-exposed side pockets, and modification of plasma membrane lipids altering channel gating. Numerous non-cardiovascular drugs have a potential to induce life-threatening torsades de pointes (TdP) ventricular cardiac arrhythmias by blocking human ether-à-go-go -related gene (hERG) currents via binding to the channel's inner cavity. Identification of the hERG current-inhibiting properties of candidate drugs is performed focusing on binding sites in the channel pore. It has been suggested that biologicals have a low likelihood of hERG current inhibition, since their poor diffusion across the plasma membrane prevents them from reaching the binding site in the channel pore. However, biologicals could influence hERG channel function by binding to 'unconventional' noncanonical binding sites. This Opinion gives an overview on noncanonical blockers of hERG channels that might be of relevance for the assessment of the possible torsadogenic potential of macromolecular therapeutics. [ABSTRACT FROM AUTHOR]

N-linked glycosylation is an essential and highly conserved co- and post-translational protein modification in all domains of life. In humans, genetic defects in N-linked glycosylation pathways result in metabolic diseases collectively called Congenital Disorders of Glycosylation. In this modification reaction, a mannose rich oligosaccharide is transferred from a lipid-linked donor substrate to a specific asparagine side-chain within the -N-X-T/S- sequence (where X ≠ Proline) of the nascent protein. Oligosaccharyltransferase (OST), a multi-subunit membrane embedded enzyme catalyzes this glycosylation reaction in eukaryotes. In yeast, Ost4 is the smallest of nine subunits and bridges the interaction of the catalytic subunit, Stt3, with Ost3 (or its homolog, Ost6). Mutations of any C-terminal hydrophobic residues in Ost4 to a charged residue destabilizes the enzyme and negatively impacts its function. Specifically, the V23D mutation results in a temperature-sensitive phenotype in yeast. Here, we report the reconstitution of both purified recombinant Ost4 and Ost4V23D each in a POPC/POPE lipid bilayer and their resonance assignments using heteronuclear 2D and 3D solid-state NMR with magic-angle spinning. The chemical shifts of Ost4 changed significantly upon the V23D mutation, suggesting a dramatic change in its chemical environment. [ABSTRACT FROM AUTHOR]

Biosensors play an important role in numerous research fields. Quartz crystal microbalances with dissipation monitoring (QCM-Ds) are sensitive devices, and binding events can be observed in real-time. In combination with aptamers, they have great potential for selective and label-free detection of various targets. In this study, an alternative surface functionalization for a QCM-D-based aptasensor was developed, which mimics an artificial cell membrane and thus creates a physiologically close environment for the binding of the target to the sensor. Vesicle spreading was used to form a supported lipid bilayer (SLB) of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphethanolamine-N-(cap biotinyl) (biotin-PE). The SLB was then coated with streptavidin followed by applying a biotinylated aptamer against thrombin. SLB formation was investigated in terms of temperature and composition. Temperatures of 25 °C and below led to incomplete SLB formation, whereas a full bilayer was built at higher temperatures. We observed only a small influence of the content of biotinylated lipids in the mixture on the further binding of streptavidin. The functionalization of the sensor surface with the thrombin aptamer and the subsequent thrombin binding were investigated at different concentrations. The sensor could be reconstituted by incubation with a 5 M urea solution, which resulted in the release of the thrombin from the sensor surface. Thereafter, it was possible to rebind thrombin. Thrombin in spiked samples of human serum was successfully detected. The developed system can be easily applied to other target analytes using the desired aptamers. [ABSTRACT FROM AUTHOR]

Cholesterol has been conjectured to be a modulator of the amyloid cascade, the mechanism that produces the amyloid-β (Aβ) peptides implicated in the onset of Alzheimer's disease. We propose that cholesterol impacts the genesis of Aβ not through direct interaction with proteins in the bilayer, but indirectly by inducing the liquid-ordered phase and accompanying liquid–liquid phase separations, which partition proteins in the amyloid cascade to different lipid domains and ultimately to different endocytotic pathways. We explore the full process of Aβ genesis in the context of liquid-ordered phases induced by cholesterol, including protein partitioning into lipid domains, mechanisms of endocytosis experienced by lipid domains and secretases, and pH-controlled activation of amyloid precursor protein secretases in specific endocytotic environments. Outstanding questions on the essential role of cholesterol in the amyloid cascade are identified for future studies. [ABSTRACT FROM AUTHOR]

ABSTRACTThis paper reviews our current understanding of how fullerene molecules interact with biological membranes. First, we discuss how fullerenes permeate into biological membranes. Next, the putative mechanisms of fullerene aggregation and dispersion within lipid bilayers are discussed along with their potential toxic effect on biological membranes. Finally, current trends in the study of fullerene-membrane interactions are highlighted as well as future challenges that need to be overcome to further advance the field.

The destructive effect of Aβ peptides on membranes is an important source of its cytotoxicity in the pathogenesis of Alzheimer's disease. We have investigated the binding mechanism between the Aβ42 peptide and bilayer in our former work. However, as another abundant form of Aβ peptides in the physiological environment, the binding mechanism between Aβ40 peptide and the lipid bilayer still remains ambiguous. Hence, we performed all-atom simulations on the Aβ40 peptides with the lipid bilayer herein using replica exchange with the solute tempering 2 method. We obtained four major binding models with the hydrophobic C-terminus as the most preferable binding region. Hydrophobic residues and positively charged residues are the principal residues involved in the peptide-bilayer interactions. Aβ40 peptides in our simulation mainly adopt a β-rich conformation in both bound and unbound states. Besides, we determined peptide-water interactions and found that bound peptides prefer forming hydrogen bonds with water molecules than unbound peptides. Our findings herein may provide new insights for the in-depth understanding of the membrane-destructive mechanism of Aβ peptides. [ABSTRACT FROM AUTHOR]

Mitochondria are most likely descendants of strictly aerobic prokaryotes from the class Alphaproteobacteria. The mitochondrial matrix is surrounded by two membranes according to its relationship with Gram-negative bacteria. Similar to the bacterial outer membrane, the mitochondrial outer membrane acts as a molecular sieve because it also contains diffusion pores. However, it is more actively involved in mitochondrial metabolism because it plays a functional role, whereas the bacterial outer membrane has only passive sieving properties. Mitochondrial porins, also known as eukaryotic porins or voltage-dependent anion-selective channels (VDACs) control the permeability properties of the mitochondrial outer membrane. They contrast with most bacterial porins because they are voltage-dependent. They switch at relatively small transmembrane potentials of 20 to 30 mV in closed states that exhibit different permeability properties than the open state. Whereas the open state is preferentially permeable to anionic metabolites of mitochondrial metabolism, the closed states prefer cationic solutes, in particular, calcium ions. Mitochondrial porins are encoded in the nucleus, synthesized at cytoplasmatic ribosomes, and post-translationally imported through special transport systems into mitochondria. Nineteen beta strands form the beta-barrel cylinders of mitochondrial and related porins. The pores contain in addition an α-helical structure at the N-terminal end of the protein that serves as a gate for the voltage-dependence. Similarly, they bind peripheral proteins that are involved in mitochondrial function and compartment formation. This means that mitochondrial porins are localized in a strategic position to control mitochondrial metabolism. The special features of the role of mitochondrial porins in apoptosis and cancer will also be discussed in this article. [ABSTRACT FROM AUTHOR]

In this study, we advance our exploration of Apolipoprotein A-I (apoA-I) peptide analogs (APAs) for their application in nanodisc (ND) assembly, focusing on the dynamic conformational characteristics and the potential for drug delivery. We explore APA-ND interactions with an emphasis on curcumin encapsulation, utilizing molecular dynamic simulations and in vitro assessments to evaluate the efficacy of various APA-ND formulations as drug carriers. The methodological approach involved the generation of three unique apoA-I α-11/3 helical mimics, resulting in fifteen distinct APAs. Their structural integrity was rigorously assessed using ColabFold-AF2, with particular attention to pLDDT and pTM scores. Extensive molecular dynamics simulations, covering 1.7 μs across 17 ND systems, were conducted to investigate the influence of APA sequence variations on ND stability and interactions. This study reveals that the composition of APAs, notably the presence of Proline, Serine, and Tryptophan, significantly impacts ND stability and morphology. Oligomeric APAs, in particular, demonstrated superior stability and distinct interaction patterns compared to their monomeric counterparts. Additionally, hydrodynamic diameter measurements over eight weeks indicated sequence-dependent stability, highlighting the potential of specific APA configurations for sustained colloidal stability. In vitro study successfully encapsulated curcumin in [AA]3/DMPC ND formulations, revealing concentration-dependent stability and interaction dynamics. The findings underscore the remarkable capability of APA-NDs to maintain structural integrity and efficient drug encapsulation, positioning them as a promising platform for drug delivery. The study concludes by emphasizing the tunability and versatility of APA-NDs in drug formulation, potentially revolutionizing nanomedicine by enabling customized APA sequences and ND properties for targeted drug delivery. [ABSTRACT FROM AUTHOR]

The human immunodeficiency virus type 1 (HIV-1) matrix protein contains a highly basic region, MA-HBR, crucial for various stages of viral replication. To elucidate the interactions between the polybasic peptide MA-HBR and lipid bilayers, we employed liquid-based atomic force microscopy (AFM) imaging and force spectroscopy on lipid bilayers of differing compositions. In 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers, AFM imaging revealed the formation of annulus-shaped protrusions upon exposure to the polybasic peptide, accompanied by distinctive mechanical responses characterized by enhanced bilayer puncture forces. Importantly, our AFM-based force spectroscopy measurements unveiled that MA-HBR induces interleaflet decoupling within the cohesive bilayer organization. This is evidenced by a force discontinuity observed within the bilayer's elastic deformation regime. In POPC/cholesterol bilayers, MA-HBR caused similar yet smaller annular protrusions, demonstrating an intriguing interplay with cholesterol-rich membranes. In contrast, in bilayers containing anionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS) lipids, MA-HBR induced unique annular protrusions, granular nanoparticles, and nanotubules, showcasing its distinctive effects in anionic lipid-enriched environments. Notably, our force spectroscopy data revealed that anionic POPS lipids weakened interleaflet adhesion within the bilayer, resulting in interleaflet decoupling, which potentially contributes to the specific bilayer perturbations induced by MA-HBR. Collectively, our findings highlight the remarkable variations in how the polybasic peptide, MA-HBR, interacts with lipid bilayers of differing compositions, shedding light on its role in host membrane restructuring during HIV-1 infection. [ABSTRACT FROM AUTHOR]

Recently, lipid nanoparticles (LNPs) have been extensively investigated as non-viral carriers of nucleic acid vaccines due to their high transport efficiency, safety, and straightforward production and scalability. However, the molecular mechanism underlying the interactions between nucleic acids and phospholipid bilayers within LNPs remains elusive. In this study, we employed the all-atom molecular dynamics simulation to investigate the interactions between single-stranded nucleic acids and a phospholipid bilayer. Our findings revealed that hydrophilic bases, specifically G in single-stranded RNA (ssRNA) and single-stranded DNA (ssDNA), displayed a higher propensity to form hydrogen bonds with phospholipid head groups. Notably, ssRNA exhibited stronger binding energy than ssDNA. Furthermore, divalent ions, particularly Ca2+, facilitated the binding of ssRNA to phospholipids due to their higher binding energy and lower dissociation rate from phospholipids. Overall, our study provides valuable insights into the molecular mechanisms underlying nucleic acid-phospholipid interactions, with potential implications for the nucleic acids in biotherapies, particularly in the context of lipid carriers. [ABSTRACT FROM AUTHOR]

Oncogenic Ras proteins are known to present multiple conformational states, as reported by the great variety of crystallographic structures. The GTP-bound states are grouped into two main states: the "inactive" state 1 and the "active" state 2. Recent reports on H-Ras have shown that state 2 exhibits two substates, directly related to the orientation of Tyr32: toward the GTP-bound pocket and outwards. In this paper, we show that N-Ras exhibits another substate of state 2, related to a third orientation of Tyr32, toward Ala18 and parallel to the GTP-bound pocket. We also show that this substate is highly sampled in the G12V mutation of N-Ras and barely present in its wild-type form, and that the G12V mutation prohibits the sampling of the GTPase-activating protein (GAP) binding substate, rendering this mutation oncogenic. Furthermore, using molecular dynamics simulations, we explore the importance of the membrane on N-Ras' conformational state dynamics and its strong influence on Ras protein stability. Moreover, the membrane has a significant influence on the conformational (sub)states sampling of Ras. This, in turn, is of crucial importance in the activation/deactivation cycle of Ras, due to the binding of guanine nucleotide exchange factor proteins (GEFs)/GTPase-activating proteins (GAPs). [ABSTRACT FROM AUTHOR]

[Display omitted] The process of protein corona changes has been widely believed to follow the Vroman effect, while protein structural change during the process is rarely reported, due to the lack of analytical methods. In-situ interpretation for protein structural change is critical to processes such as the recognition and transport of nanomaterials. Molecular dynamics (MD) simulation was used to predict the deflection and twist of the protein tertiary structure. The structural changes of the surface protein corona during the interaction of nanoparticles (NPs) with lipid bilayer were probed in situ and real-time by sum frequency generation (SFG) spectroscopy. The ring tertiary structure of the protein corona is altered from vertical to horizontal on particle surface, a process of the soft-to-hard structural transition, which is contributed by the hydrogen bonding force between the protein and water molecules. The negatively charged protein corona can induce the redistribution of interfacial charge, leading to a more stable hydrogen bond network of the interfacial water. Our findings suggest that the structural change from flexible to rigid is a crucial process in the soft-to-hard transition of the protein corona, which will be a beneficial supplement to the Vroman effect of protein adsorption. [ABSTRACT FROM AUTHOR]

Cell membranes are composed of a large variety of lipids and proteins. While the localization and function of membrane proteins have been extensively investigated, the distribution of membrane lipids, especially in the non-cytoplasmic leaflet of organelle membranes, remains largely unknown. Fluorescent biosensors have been widely used to study membrane lipid distribution; however, they have some limitations. By utilizing the quick-freezing and freeze-fracture replica labeling electron microscopy technique, we can uncover the precise distribution of membrane lipids within cells and assess the function of lipid-transporting proteins. In this review, I summarize recent progress in analyzing intracellular lipid distribution by utilizing this method. [ABSTRACT FROM AUTHOR]

Biomembranes consisting of two opposing phospholipid monolayers, which comprise the so-called lipid bilayer, are largely responsible for the dual solid-fluid behavior of individual cells and viruses. Quantifying the mechanical characteristics of biomembrane, including the dynamics of their in-plane fluidity, can provide insight not only into active or passive cell behaviors but also into vesicle design for drug delivery systems. Despite numerous studies on the mechanics of biomembranes, their dynamical viscoelastic properties have not yet been fully described. We thus quantify their viscoelasticity based on a two-dimensional (2D) fluid membrane model, and investigate this viscoelasticity under small amplitude oscillatory loadings in micron-scale membrane area. We use hydrodynamic equations of bilayer membranes, obtained by Onsager's variational principle, wherein the fluid membrane is assumed to be an almost planar bilayer membrane. Simulations are performed for a wide range of oscillatory frequencies f and membrane tensions. Our numerical results show that as frequencies increase, membrane characteristics shift from an elastic-dominant to viscous-dominant state. Furthermore, such state transitions obtained with a 1-μm-wide loading profile appear with frequencies between O(f)=101–102 Hz, and almost independently of surface tensions. We discuss the formation mechanism of the viscous- or elastic-dominant transition based on relaxation rates that correspond to the eigenvalues of the dynamical matrix in the governing equations.

Cancerous tissues undergo extensive changes to their cellular environments that differentiate them from healthy tissues. These changes include changes in extracellular pH and Ca2+ concentrations, and the exposure of phosphatidylserine (PS) to the extracellular environment, which can modulate the interaction of peptides and proteins with the plasma membrane. Deciphering the molecular mechanisms of such interactions is critical for advancing the knowledge-based design of cancer-targeting molecular tools, such as pH-low insertion peptide (pHLIP). Here, we explore the effects of PS, Ca2+ , and peptide protonation state on the interactions of pHLIP with lipid membranes. Cellular studies demonstrate that exposed PS on the plasma membrane promotes pHLIP targeting. The magnitude of this effect is dependent on extracellular Ca2+ concentration, indicating that divalent cations play an important role in pHLIP targeting in vivo. The targeting mechanism is further explored with a combination of fluorescence and circular dichroism experiments in model membranes and microsecond-timescale all-atom molecular dynamics simulations. Our results demonstrate that Ca2+ is engaged in coupling peptide-lipid interactions in the unprotonated transmembrane conformation of pHLIP. The simulations reveal that while the pH-induced insertion leads to a strong depletion of PS around pHLIP, the Ca2+ -induced insertion has the opposite effect. Thus, extracellular levels of Ca2+ are crucial to linking cellular changes in membrane lipid composition with the selective targeting and insertion of pHLIP. The characterized Ca2+ -dependent coupling between pHLIP sidechains and PS provides atomistic insights into the general mechanism for lipid-coupled regulation of protein-membrane insertion by divalent cations.

The widely used Laurdan probe has two conformers, resulting in different optical properties when embedded in a lipid bilayer membrane, as demonstrated by our previous simulations. Up to now, the two conformers’ optical responses have, however, not been investigated when the temperature and the phase of the membrane change. Since Laurdan is known to be both a molecular rotor and a solvatochromic probe, it is subject to a profound interaction with both neighboring lipids and water molecules. In the current study, molecular dynamics simulations and hybrid Quantum Mechanics/Molecular Mechanics calculations are performed for a DPPC membrane at eight temperatures between 270K and 320K, while the position, orientation, fluorescence lifetime and fluorescence anisotropy of the embedded probes are monitored. The importance of both conformers is proven through a stringent comparison with experiments, which corroborates the theoretical findings. It is seen that for Conf-I, the excited state lifetime is longer than the relaxation of the environment, while for Conf-II, the surroundings are not yet adapted when the probe returns to the ground state. Throughout the temperature range, the lifetime and anisotropy decay curves can be used to identify the different membrane phases. The current work might, therefore, be of importance for biomedical studies on diseases, which are associated with cell membrane transformations.

Reservoir computing is a highly efficient machine learning framework for processing temporal data by extracting input features and mapping them into higher dimensional spaces. Physical reservoirs have been realized using spintronic oscillators, atomic switch networks, volatile memristors, etc. However, these devices are intrinsically energy‐dissipative due to their resistive nature, increasing their power consumption. Therefore, memcapacitive devices can provide a more energy‐efficient approach. Herein, volatile biomembrane‐based memcapacitors are leveraged as reservoirs to solve classification tasks and process time series in simulation and experimentally. This system achieves a 99.6% accuracy for spoken‐digit classification and a normalized mean square error of 7.81×10−4$7.81 \times \left(10\right)^{- 4}$ in a second‐order nonlinear regression task. Furthermore, to showcase the device's real‐time temporal data processing capability, a 100% accuracy for an epilepsy detection problem is achieved. Most importantly, it is demonstrated that each memcapacitor consumes an average of 41.5 fJ of energy per spike, regardless of the selected input voltage pulse width, while maintaining an average power of 415 fW for a pulse width of 100 ms, orders of magnitude lower than those achieved by state‐of‐the‐art devices. Lastly, it is believed that the biocompatible, soft nature of our memcapacitor renders it highly suitable for computing applications in biological environments. [ABSTRACT FROM AUTHOR]

Bioactive peptides have emerged as promising therapeutic agents with antimicrobial, antifungal, antiparasitic, and, recently, antitumoral properties with a mechanism of action based on membrane destabilization and cell death, often involving a conformational change in the peptide. This biophysical study aims to provide preliminary insights into the membrane-level antitumoral mode of action of crotalicidin, a cationic host defense peptide from rattlesnake venom, toward breast cancer cell lines. The lipid composition of breast cancer cell lines was obtained after lipid extraction and quantification to prepare representative cell membrane models. Membrane–peptide interaction studies were performed using differential scanning calorimetry and Fourier-transform infrared spectroscopy. The outcome evidences the potential antitumoral activity and selectivity of crotalicidin toward breast cancer cell lines and suggests a mechanism initiated by the electrostatic interaction of the peptide with the lipid bilayer surface and posterior conformation change with membrane intercalation between the acyl chains in negatively charged lipid systems. This research provides valuable information that clears up the antitumoral mode of action of crotalicidin. [ABSTRACT FROM AUTHOR]

P-glycoprotein (Pgp) plays a pivotal role in drug bioavailability and multi-drug resistance development. Understanding the protein's activity and designing effective drugs require insight into the mechanisms underlying Pgp-mediated transport of xenobiotics. In this study, we investigated the drug-induced conformational changes in Pgp and adopted a conformationally-gated model to elucidate the Pgp-mediated transport of camptothecin analogs (CPTs). While Pgp displays a wide range of conformations, we simplified it into three model states: 'open-inward', 'open-outward', and 'intermediate'. Utilizing acrylamide quenching of Pgp fluorescence as a tool to examine the protein's tertiary structure, we observed that topotecan (TPT), SN-38, and irinotecan (IRT) induced distinct conformational shifts in the protein. TPT caused a substantial shift akin to AMPPNP, suggesting ATP-independent 'open-outward' conformation. IRT and SN-38 had relatively moderate effects on the conformation of Pgp. Experimental atomic force microscopy (AFM) imaging supports these findings. Further, the rate of ATPase hydrolysis was correlated with ligand-induced Pgp conformational changes. We hypothesize that the separation between the nucleotide-binding domains (NBDs) creates a conformational barrier for substrate transport. Substrates that reduce the conformational barrier, like TPT, are better transported. The affinity for ATP extracted from Pgp-mediated ATP hydrolysis kinetics curves for TPT was about 2-fold and 3-fold higher than SN-38 and IRT, respectively. On the contrary, the dissociation constants (KD) determined by fluorescence quenching for these drugs were not significantly different. Saturation transfer double difference (STDD) NMR of TPT and IRT with Pgp revealed that similar functional groups of the CPTs are accountable for Pgp-CPTs interactions. Efforts aimed at modifying these functional groups, guided by available structure-activity relationship data for CPTs and DNA-Topoisomerase-I complexes, could pave the way for the development of more potent next-generation CPTs. [ABSTRACT FROM AUTHOR]

We describe the concept and roadmap of an engineered electronic nose with specificity towards analytes that differ by as little as one carbon atom, and sensitivity of being able to electrically register a single molecule of analyte. The analyte could be anything that natural noses can detect, e.g. trinitrotoluene (TNT), cocaine, aromatics, volatile organic compounds etc. The strategy envisioned is to genetically engineer a fused olfactory odorant receptor (odorant receptor (OR), a membrane-bound G-protein coupled receptor (GPCR) with high selectivity) to an ion channel protein, which opens in response to binding of the ligand to the OR. The lipid bilayer supporting the fused sensing protein would be intimately attached to a nanowire or nanotube network (either via a covalent tether or a non-covalent physisorption process), which would electrically detect the opening of the ion channel, and hence the binding of a single ligand to a single OR protein domain. Three man-made technological advances: (1) fused GPCR to ion channel protein, (2) nanowire sensing of single ion channel activity, and (3) lipid bilayer to nanotube/nanowire tethering chemistry and on natural technology (sensitivity and selectivity of OR domains to specific analytes) each have been demonstrated and/or studied independently. The combination of these three technological advances and the result of millions of years of evolution of OR proteins would enable the goal of single molecule sensing with specificity towards analytes that differ by as little as one carbon atom. This is both a review of the past and a vision of the future. [ABSTRACT FROM AUTHOR]

The myelin sheath provides insulation to the brain's neuron cells, which aids in signal transmission and communication with the body. Degenerated myelin hampers the connection between the glial cells, which are the front row responders during traumatic brain injury mitigation. Thus, the structural integrity of the myelin layer is critical for protecting the brain tissue from traumatic injury. At the molecular level, myelin consists of a lipid bilayer, myelin basic proteins (MBP), proteolipid proteins (PLP), water and ions. Structurally, the myelin sheath is formed by repeatedly wrapping forty or more myelin layers around an axon. Here, we have used molecular dynamic simulations to model and capture the tensile response of a single myelin layer. An openly available molecular dynamic solver, LAMMPS, was used to conduct the simulations. The interatomic potentials for the interacting atoms and molecules were defined using CHARMM force fields. Following a standard equilibration process, the molecular model was stretched uniaxially at a deformation rate of 5 Å/ps. We observed that, at around 10% applied strain, the myelin started to cohesively fail via flaw formation inside the bilayers. Further stretching led to a continued expansion of the defect inside the bilayer, both radially and transversely. This study provides the cellular-level mechanisms of myelin damage due to mechanical load. [ABSTRACT FROM AUTHOR]

Consistent buckling distortions of a large membrane patch (200 × 200 Å) are observed during molecular dynamics (MD) simulations using the Monte-Carlo (MC) barostat in combination with a hard Lennard-Jones (LJ) cutoff. The buckling behavior is independent of both the simulation engine and the force field but requires the MC barostat-hard LJ cutoff combination. Similar simulations of a smaller patch (90 × 90 Å) do not show buckling, but do show a small, systematic reduction in the surface area accompanied by ~1 Å thickening suggestive of compression. We show that a mismatch in the way potentials and forces are handled in the dynamical equations versus the MC barostat results in a compressive load on the membrane. Moreover, a straightforward application of elasticity theory reveals that a minimal compression of the linear dimensions of the membrane, inversely proportional to the edge length, is required for buckling, explaining this differential behavior. We recommend always using LJ force or potential-switching when the MC barostat is employed to avoid undesirable membrane deformations.

In this research, we have used the dissipative particle dynamics (DPD), a mesoscopic simulation technique, in order to investigate the dynamics of lipid domains in near critical temperature. Our specific focus has been on exploring the influence of lipid domain size on its lifetime, which mimics the behavior of lipid rafts within cellular membranes. The lipid membranes used in this study were composed of saturated and unsaturated lipids, which have been immersed in water. Through the simulation of these membranes close to their critical temperature, we have successfully generated fluctuating domains that mimic the lipid rafts observed in cellular systems. We have proposed a method to obtain the lifetime of the fluctuating domains by analyzing the sizes of the lipid domains at specific intervals of time. Our investigations have revealed a linear correlation between the initial size of the lipid domain and its lifetime. Our research finding give an insight into the underlying mechanisms that govern lipid rafts and their vital role in various cellular processes.

Biosensors play an important role in numerous research fields. Quartz crystal microbalances with dissipation monitoring (QCM-Ds) are sensitive devices, and binding events can be observed in real-time. In combination with aptamers, they have great potential for selective and label-free detection of various targets. In this study, an alternative surface functionalization for a QCM-D-based aptasensor was developed, which mimics an artificial cell membrane and thus creates a physiologically close environment for the binding of the target to the sensor. Vesicle spreading was used to form a supported lipid bilayer (SLB) of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphethanolamine-N-(cap biotinyl) (biotin-PE). The SLB was then coated with streptavidin followed by applying a biotinylated aptamer against thrombin. SLB formation was investigated in terms of temperature and composition. Temperatures of 25 °C and below led to incomplete SLB formation, whereas a full bilayer was built at higher temperatures. We observed only a small influence of the content of biotinylated lipids in the mixture on the further binding of streptavidin. The functionalization of the sensor surface with the thrombin aptamer and the subsequent thrombin binding were investigated at different concentrations. The sensor could be reconstituted by incubation with a 5 M urea solution, which resulted in the release of the thrombin from the sensor surface. Thereafter, it was possible to rebind thrombin. Thrombin in spiked samples of human serum was successfully detected. The developed system can be easily applied to other target analytes using the desired aptamers.

Reservoir computing is a highly efficient machine learning framework for processing temporal data by extracting input features and mapping them into higher dimensional spaces. Physical reservoirs have been realized using spintronic oscillators, atomic switch networks, volatile memristors, etc. However, these devices are intrinsically energy‐dissipative due to their resistive nature, increasing their power consumption. Therefore, memcapacitive devices can provide a more energy‐efficient approach. Herein, volatile biomembrane‐based memcapacitors are leveraged as reservoirs to solve classification tasks and process time series in simulation and experimentally. This system achieves a 99.6% accuracy for spoken‐digit classification and a normalized mean square error of 7.81×10−4 in a second‐order nonlinear regression task. Furthermore, to showcase the device's real‐time temporal data processing capability, a 100% accuracy for an epilepsy detection problem is achieved. Most importantly, it is demonstrated that each memcapacitor consumes an average of 41.5 fJ of energy per spike, regardless of the selected input voltage pulse width, while maintaining an average power of 415 fW for a pulse width of 100 ms, orders of magnitude lower than those achieved by state‐of‐the‐art devices. Lastly, it is believed that the biocompatible, soft nature of our memcapacitor renders it highly suitable for computing applications in biological environments.

The mu-opioid receptor (MOR) is a transmembrane protein and the primary target for pain-modulating drugs. Opioid drugs come with detrimental side-effects such as physical dependence and addiction. However, recent studies show that understanding structural properties and dynamics of MOR may aid in the design of opioid drugs with reduced side effects. Molecular dynamics simulations allow researchers to study changes in protein conformation at an atomistic level. However, modeling systems including MOR embedded in a lipid bilayer can be computationally expensive. This study evaluates a modeling approach that uses harmonic restraints on the transmembrane regions of MOR to model the rigidity of the lipid bilayer without explicitly simulating lipid molecules, reducing the number of atoms in the simulation. The proposed model allows MOR to be simulated 49% faster than a simulation explicitly including the lipid bilayer. To assess the accuracy of the proposed model, simulations were performed of MOR in a lipid bilayer, the free MOR in water and MOR in water with harmonic restraints applied to all transmembrane residues using NAMD 3.0 alpha and the CHARMM36 force field. Dynamic properties of MOR were shown to be different in each system, with the free MOR having a higher root mean square deviation (RMSD) than MOR with an explicitly modeled lipid bilayer. The systems with harmonic restraint constants of 0.001 kcal/mol/Å2 applied to the transmembrane residues had RMSD values comparable to those in an explicitly modeled lipid bilayer. This study demonstrates that using restraints on the transmembrane residues of MOR is a feasible way of modeling the ligand-free receptor with reduced computational costs. This model could allow the dynamics of MOR in a lipid bilayer environment to be studied more efficiently. [ABSTRACT FROM AUTHOR]

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) from the group of phenylacetic acid derivatives, which has analgesic, anti-inflammatory and antipyretic properties. The interaction of non-steroidal anti-inflammatory drugs with cell membranes can affect their physicochemical properties, which, in turn, can cause a number of side effects in the use of these drugs. Electron paramagnetic resonance (EPR) spectroscopy could be used to study the interaction of diclofenac with a membrane, if its spin-labeled analogs existed. This paper describes the synthesis of spin-labeled diclofenac (diclofenac-SL), which consists of a simple sequence of transformations such as iodination, esterification, Sonogashira cross-coupling, oxidation and saponification. EPR spectra showed that diclofenac-SL binds to a lipid membrane composed of palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). 2H electron spin echo spectroscopy (ESEEM) was used to determine the position of the diclofenac-SL relative to the membrane surface. It was established that its average depth of immersion corresponds to the 5th position of the carbon atom in the lipid chain. [ABSTRACT FROM AUTHOR]

In molecular dynamics simulations of membrane systems, it is very important to evaluate the interactions between membrane bilayers and other molecules like small compounds, peptides, or proteins. When these interactions lead to local deformations in the membrane, it is essential to fully understand and accurately characterize them, since these deformations can impact the calculation of membrane properties. Here, we introduce MembIT, a simple standalone tool that calculates several membrane properties that are very useful to gauge system equilibration and quality control in molecular dynamics simulations. It has implemented a distinction between local and bulk lipids, which corrects the local deformations, that are often overlooked by other tools. We show examples of MembIT calculations of membrane insertion and deformation values in systems containing POPC and a small drug (sunitinib), a transmembrane peptide (pHLIP), and a transmembrane protein (ADP/ATP carrier). We hope that this tool will be adopted by the scientific community and that the analyses that it provides become good practices in MD simulations of membrane systems. We present a simple standalone tool (MembIT) that calculates several membrane properties from MD simulations. It is useful for studying the membrane thickness, insertion, and deformation induced by different solutes. We showcased its application on three different systems containing sunitinib, pHLIP, or the ADP/ATP carrier in a POPC bilayer. [ABSTRACT FROM AUTHOR]

[Display omitted] Although solubilization of lipid membranes has been studied extensively, questions remain regarding the structural pathways and metastable structures involved. This study investigated whether the non-ionic detergent Triton X-100 follows the classical solubilization pathway or if intermediate nanostructures are formed. Small angle X-ray and neutron scattering (SAXS/SANS) was used in combination with transmission electron cryo-microscopy and cryo-tomography to deduce the structure of mixtures of 1,2-dipalmitoyl- sn - glycero -3-phosphocholine (DPPC) vesicles and Triton X-100. Time-resolved SAXS and dynamic light scattering were used to investigate the kinetics of the process. Upon addition of moderate detergent amounts at low temperatures, the lipid vesicles implode into ordered rippled bilamellar disc structures. The bilayers arrange in a ripple phase to accommodate packing constraints caused by inserted TX-100 molecules. The collapse is suggested to occur through a combination of water structure destabilization by detergents flipping across the membrane and osmotic pressure causing interbilayer attraction internally. The subsequently induced ripples then stabilize the aggregates and prevent solubilization, supported by the observation that negatively charged vesicles undergo a different pathway upon TX-100 addition, forming large bicelles. The findings demonstrate the richness in assembly pathways of simple lipids and detergents and stimulate considerations for the use of certain detergents in membrane solubilization. [ABSTRACT FROM AUTHOR]

Dendritic spines are small, bulbous protrusions along the dendrites of neurons and are sites of excitatory postsynaptic activity. The morphology of spines has been implicated in their function in synaptic plasticity and their shapes have been well-characterized, but the potential mechanics underlying their shape development and maintenance have not yet been fully understood. In this work, we explore the mechanical principles that could underlie specific shapes using a minimal biophysical model of membrane-actin interactions. Using this model, we first identify the possible force regimes that give rise to the classic spine shapes-stubby, filopodia, thin, and mushroom-shaped spines. We also use this model to investigate how the spine neck might be stabilized using periodic rings of actin or associated proteins. Finally, we use this model to predict that the cooperation between force generation and ring structures can regulate the energy landscape of spine shapes across a wide range of tensions. Thus, our study provides insights into how mechanical aspects of actin-mediated force generation and tension can play critical roles in spine shape maintenance.

We consider a liposome filled with the aqueous solution of an osmotic solute enclosed in a large water bath. Due to osmotic pressure, it works according to a sequence of cycles with two stages. In the first stage, the lipid vesicle with a certain input concentration of the osmotic substance is swelling up in an osmotic process until it reaches a size, when one pore is formed on its surface. The second stage follows, where the vesicle content is partially eliminated through the pore to induce a decrease in the vesicle volume up to its original size. If we take into account that the pore has two stages in its evolution, then the relaxing stage may be divided into two new stages. The swelling of the liposome is described by a differential equation. All the processes which contribute to the vesicle relaxing and its return to the initial size are described by three differential equations.

The interaction of many peptides with lipid bilayer membranes strongly depends on the lipid composition. Here, a study of the impact of unsaturated lipid acyl chains on the interaction of a derivative of the HIV-1 fusion peptide with lipid bilayer vesicles is presented. Lipid bilayer vesicles composed of mixtures of lipids with two saturated acyl chains and lipids and one saturated and one unsaturated acyl chain, but identical head groups, were studied. The dependence of the peptide conformation on the unsaturated lipid content was probed by circular dichroism spectroscopy, while the impact of the peptide on the bilayer structure was determined by small-angle neutron scattering. The impact of the peptide on the lipid bilayer vesicle dynamics was investigated using neutron spin echo spectroscopy. Molecular dynamics simulations were used to characterize the behavior of the systems studied to determine if there were clear differences in their physical properties. The results reveal that the peptide–bilayer interaction is not a simple function of the unsaturated lipid acyl chain content of the bilayer. Instead, the peptide behavior is more consistent with that seen for the bilayer containing only unsaturated lipids, which is supported by lipid-specific interactions revealed by the simulations.

Hierarchical assembly of building blocks via competing, orthogonal interactions is a hallmark of many of nature's composite materials that do not require highly specific ligand-receptor interactions. To mimic this assembly mechanism requires the development of building blocks capable of tunable interactions. In the present work, we explored the interplay between repulsive (steric and electrostatic) and attractive hydrophobic forces. The designed building blocks allow hydrophobic forces to effectively act at controlled, large distances, to create and tune the assembly of membrane-based building blocks under dilute conditions, and to affect their interactions with cellular membranes via physical cross-bridges. Specifically, we employed double-end-anchored poly(ethylene glycol)s (DEA-PEGs)-hydrophilic PEG tethers with hydrophobic tails on both ends. Using differential-interference-contrast optical microscopy, synchrotron small-angle X-ray scattering (SAXS), and cryogenic electron microscopy, we investigated the ability of DEA-PEGs to mediate assembly in the dilute regime on multiple length scales and on practical time scales. The PEG length, anchor hydrophobicity, and molar fraction of DEA-PEG molecules within a membrane strongly affect the assembly properties. Additional tuning of the intermembrane interactions can be achieved by adding repulsive interactions via PEG-lipids (steric) or cationic lipids to the DEA-PEG-mediated attractions. While the optical and electron microscopy imaging methods provided qualitative evidence of the ability of DEA-PEGs to assemble liposomes, the SAXS measurements and quantitative line-shape analysis in dilute preparations demonstrated that the ensemble average of loosely organized liposomal assemblies maintains DEA-PEG concentration-dependent tethering on defined nanometer length scales. For cationic liposome-DNA nanoparticles (CL-DNA NPs), aggregation induced by DEA-PEGs decreased internalization of NPs by cells, but tuning the DEA-PEG-induced attractions by adding repulsive steric interactions via PEG-lipids limited aggregation and increased NP uptake. Furthermore, confocal microscopy imaging together with colocalization studies with Rab11 and LysoTracker as markers of intracellular pathways showed that modifying CL-DNA NPs with DEA-PEGs alters their interactions with the plasma and endosomal membranes.

Mitochondria are most likely descendants of strictly aerobic prokaryotes from the class Alphaproteobacteria. The mitochondrial matrix is surrounded by two membranes according to its relationship with Gram-negative bacteria. Similar to the bacterial outer membrane, the mitochondrial outer membrane acts as a molecular sieve because it also contains diffusion pores. However, it is more actively involved in mitochondrial metabolism because it plays a functional role, whereas the bacterial outer membrane has only passive sieving properties. Mitochondrial porins, also known as eukaryotic porins or voltage-dependent anion-selective channels (VDACs) control the permeability properties of the mitochondrial outer membrane. They contrast with most bacterial porins because they are voltage-dependent. They switch at relatively small transmembrane potentials of 20 to 30 mV in closed states that exhibit different permeability properties than the open state. Whereas the open state is preferentially permeable to anionic metabolites of mitochondrial metabolism, the closed states prefer cationic solutes, in particular, calcium ions. Mitochondrial porins are encoded in the nucleus, synthesized at cytoplasmatic ribosomes, and post-translationally imported through special transport systems into mitochondria. Nineteen beta strands form the beta-barrel cylinders of mitochondrial and related porins. The pores contain in addition an α-helical structure at the N-terminal end of the protein that serves as a gate for the voltage-dependence. Similarly, they bind peripheral proteins that are involved in mitochondrial function and compartment formation. This means that mitochondrial porins are localized in a strategic position to control mitochondrial metabolism. The special features of the role of mitochondrial porins in apoptosis and cancer will also be discussed in this article.

In this study, we advance our exploration of Apolipoprotein A-I (apoA-I) peptide analogs (APAs) for their application in nanodisc (ND) assembly, focusing on the dynamic conformational characteristics and the potential for drug delivery. We explore APA-ND interactions with an emphasis on curcumin encapsulation, utilizing molecular dynamic simulations and in vitro assessments to evaluate the efficacy of various APA-ND formulations as drug carriers. The methodological approach involved the generation of three unique apoA-I α-11/3 helical mimics, resulting in fifteen distinct APAs. Their structural integrity was rigorously assessed using ColabFold-AF2, with particular attention to pLDDT and pTM scores. Extensive molecular dynamics simulations, covering 1.7 μs across 17 ND systems, were conducted to investigate the influence of APA sequence variations on ND stability and interactions. This study reveals that the composition of APAs, notably the presence of Proline, Serine, and Tryptophan, significantly impacts ND stability and morphology. Oligomeric APAs, in particular, demonstrated superior stability and distinct interaction patterns compared to their monomeric counterparts. Additionally, hydrodynamic diameter measurements over eight weeks indicated sequence-dependent stability, highlighting the potential of specific APA configurations for sustained colloidal stability. In vitro study successfully encapsulated curcumin in [AA]3/DMPC ND formulations, revealing concentration-dependent stability and interaction dynamics. The findings underscore the remarkable capability of APA-NDs to maintain structural integrity and efficient drug encapsulation, positioning them as a promising platform for drug delivery. The study concludes by emphasizing the tunability and versatility of APA-NDs in drug formulation, potentially revolutionizing nanomedicine by enabling customized APA sequences and ND properties for targeted drug delivery.

Oncogenic Ras proteins are known to present multiple conformational states, as reported by the great variety of crystallographic structures. The GTP-bound states are grouped into two main states: the “inactive” state 1 and the “active” state 2. Recent reports on H-Ras have shown that state 2 exhibits two substates, directly related to the orientation of Tyr32: toward the GTP-bound pocket and outwards. In this paper, we show that N-Ras exhibits another substate of state 2, related to a third orientation of Tyr32, toward Ala18 and parallel to the GTP-bound pocket. We also show that this substate is highly sampled in the G12V mutation of N-Ras and barely present in its wild-type form, and that the G12V mutation prohibits the sampling of the GTPase-activating protein (GAP) binding substate, rendering this mutation oncogenic. Furthermore, using molecular dynamics simulations, we explore the importance of the membrane on N-Ras’ conformational state dynamics and its strong influence on Ras protein stability. Moreover, the membrane has a significant influence on the conformational (sub)states sampling of Ras. This, in turn, is of crucial importance in the activation/deactivation cycle of Ras, due to the binding of guanine nucleotide exchange factor proteins (GEFs)/GTPase-activating proteins (GAPs).

Graphene oxide (GO) causes unique phenomena in the adsorption, structural transformation, and intramembrane domain distribution of lipid bilayer membranes. The amphiphilic surface property of GO because of nanoscale patches of pristine graphene and oxygen-functionalized regions affects the assembly of amphiphilic lipid molecules in the bimolecular membrane. Spherical vesicles of phosphatidylcholine (PC) transformed to a single bilayer, doubly stacking bilayer, or intact vesicles on GO depending on the surrounding condition. In a binary lipid bilayer comprising PC and a lipid tagged with polyethylene glycol (PEG), the domain of the PEG-tagged lipid preferentially localized on GO. The results about the interaction between GO and artificial lipid bilayer membranes provide fundamental information for understanding compatibility and/or toxicity of GO on cells and organelles. [ABSTRACT FROM AUTHOR]

Membrane proteins are attractive targets for drug discovery due to their crucial roles in various biological processes. Studying the binding poses of amphipathic molecules to membrane proteins is essential for understanding the functions of membrane proteins and docking simulations can facilitate the screening of protein–ligand complexes at low computational costs. However, identifying docking poses for a ligand in non-aqueous environments such as lipid bilayers can be challenging. To address this issue, we propose a new docking score called logP-corrected membrane docking (LoCoMock) score. To screen putative protein–ligand complexes embedded in a membrane, the LoCoMock score considers the affinity between a target ligand and the membrane. It combines the docking score of the protein–ligand complex with the logP of the target ligand. In demonstrations using several model ligands, the LoCoMock score screened more putative complexes than the conventional docking score. As extended docking, the LoCoMock score makes it possible to screen membrane proteins more effectively as drug targets than the conventional docking. [ABSTRACT FROM AUTHOR]

MC-PDGI/PAAm gels are cylindrical composite gels containing poly(dodecyl glyceryl itaconate) (PDGI) as a polymerized lipid oriented in a multilayer tubular shape within a polyacrylamide (PAAm) network. The most unique feature of the MC-PDGI/PAAm gel is its super-anisotropic swelling, wherein the diameter of the gel increases, but the length decreases with an increase in the volume of the gel. Through swelling and small-angle X-ray diffraction experiments, we investigated the effects of PDGI lipid bilayers and polymer network on the swelling of the MC-PDGI/PAAm gel, which suggests that the swelling anisotropy of the MC-PDGI/PAAm gel is dominated by the elasticity of the PDGI bilayers. Furthermore, we investigated the equation of state of the gel that roughly reproduced the experimental swelling results. These findings are crucial for realizing the controlled super-anisotropic swelling of MC-PDGI/PAAm gels and their applications as anisotropic actuation devices. [ABSTRACT FROM AUTHOR]

The morphinomimetic properties of hemorphins are intensively studied with regard to new peptide drug developments. In this respect, the investigation of mechanical properties and stability of lipid membranes provides a useful background for advancement in pharmacological applications of liposomes. Here we probed the effect of the endogenous heptapeptide VV-hemorphin-5 (valorphin) on the bending elasticity of biomimetic lipid membranes of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) by analysis of thermal shape fluctuations of nearly spherical giant unilamellar vesicles. In a wide concentration range covering valorphin concentrations applied in nociceptive screening in vivo, we report alterations of the bilayer bending rigidity in a concentration-dependent non-monotonic manner. We performed quantitative characterization of VV-hemorphin-5 association to POPC membranes by isothermal titration calorimetry in order to shed light on the partitioning of the amphiphilic hemorphin between the aqueous solution and membranes. The calorimetric results correlate with flicker spectroscopy findings and support the hypothesis about the strength of valorphin-membrane interaction related to the peptide bulk concentration. A higher strength of valorphin interaction with the bilayer corresponds to a more pronounced effect of the peptide on the membrane's mechanical properties. The presented study features the comprehensive analysis of membrane bending elasticity as a biomarker for physicochemical effects of peptides on lipid bilayers. The reported data on thermodynamic parameters of valorphin interactions with phosphatidylcholine bilayers and alterations of their mechanical properties is expected to be useful for applications of lipid membrane systems in pharmacology and biomedicine.

Abstract Aims The Blood-Brain Barrier (BBB) is a filter for most medications and blocks their passage into the brain. More effective drug delivery strategies are urgently needed to transport medications into the brain. This study investigated the biodistribution of thymoquinone (TQ) and the effect on enzymatic and non-enzymatic oxidative stress indicators in different brain regions, either in free form or incorporated into nanocarriers as mesoporous silica nanoparticles (MSNs). Lipid bilayer-coated MSNs. Materials and methods MSNs and LB-MSNs were synthesized and characterized using a transmission electron microscope and dynamic light scattering to determine the particle size and zeta potential. TQ encapsulation efficiency and TQ's release profile from LB-MSNs were also examined. The impact of loading LB-MSNs with TQ-on-TQ delivery to different brain areas was examined using chromatographic measurement. Furthermore, nitric oxide, malondialdehyde (MDA), reduced glutathione, and catalase were evaluated as oxidant and antioxidant stress biomarkers. Key findings The LB-MSNs formulation successfully transported TQ to several areas of the brain, liver, and kidney, revealing a considerable increase in TQ delivery in the thalamus (81.74%) compared with that in the free TQ group and a considerable reduction in the cortex (−44%). The LB-MSNs formulation had no significant effect on TQ delivery in the cerebellum, striatum, liver, and kidney. Significance TQ was redistributed in different brain areas after being encapsulated in LB-MSNs, indicating that LB-MSNs have the potential to be developed as a drug delivery system for selective clinical application of specific brain regions. Conclusions LB-MSNs are capable nanoplatforms that can be used to target medications precisely to specific brain regions