Gramicidin S (GS), one of the first discovered antimicrobial peptides, still shows strong antibiotic activity after decades of clinical use, with no evidence of resistance. The relatively high hemolytic activity and narrow therapeutic window of GS limit its use in topical applications. Encapsulation and targeted delivery may be the way to develop the internal administration of this drug. The lipid composition of membranes and non-covalent interactions affect GS\'s affinity for and partitioning into lipid bilayers as monomers or oligomers, which are crucial for GS activity. Using both differential scanning calorimetry (DSC) and FTIR methods, the impact of GS on dipalmitoylphosphatidylcholine (DPPC) membranes was tested. Additionally, the combined effect of GS and cholesterol on membrane characteristics was observed; while dipalmitoylphosphatydylglycerol (DPPG) and cerebrosides did not affect GS binding to DPPC membranes, cholesterol significantly altered the membrane, with 30% mol concentration being most effective in enhancing GS binding. The effect of star-like dextran-polyacrylamide D-g-PAA(PE) on GS binding to the membrane was tested, revealing that it interacted with GS in the membrane and significantly increased the proportion of GS oligomers. Instead, calcium ions affected GS binding to the membrane differently, with independent binding of calcium and GS and no interaction between them. This study shows how GS interactions with lipid membranes can be effectively modulated, potentially leading to new formulations for internal GS administration. Modified liposomes or polymer nanocarriers for targeted GS delivery could be used to treat protein misfolding disorders and inflammatory conditions associated with free-radical processes in cell membranes.

The swelling and collapse of responsive nanogels on a planar lipid bilayer are studied by means of mesoscopic computer simulations. The effects of molecular weight, cross-linking density, and adhesion strength are examined. The conditions for collapse-mediated engulfing by the bilayer are found. In particular, the results show that at low hydrophobicity level the increase in the nanogel softness decreases the engulfing rate. On the contrary, for stronger hydrophobicity level the trend changes to the opposite one. At the same time, when the cross-linking density is too low or the adhesion strength is too high the nanogel deformation at the membrane suppresses the engulfing regardless of the network swelling ratio. Finally, for comparative reasons, the behavior of the nanogels is also studied at the solid surface. These results may be useful in the design of soft particles capable of tuning of their elasticity and porosity for successful intracellular drug delivery.

Glycyrrhizinic acid (GA) is one of the active substances in licorice root. It exhibits antiviral activity against various enveloped viruses, for example, SARS-CoV-2. GA derivatives are promising biologically active compounds from perspective of developing broad-spectrum antiviral agents. Given that GA nicotinate derivatives (Glycyvir) demonstrate activity against various DNA- and RNA-viruses, a search for a possible mechanism of action of these compounds is required. In the present paper, the interaction of Glycyvir with the transmembrane domain of the SARS-CoV-2 E-protein (ETM) in a model lipid membrane was investigated by NMR spectroscopy and molecular dynamics simulation. The lipid-mediated influence on localization of the SARS-CoV-2 E-protein by Glycyvir was observed. The presence of Glycyvir leads to deeper immersion of the ETM in lipid bilayer. Taking into account that E-protein plays a significant role in virus production and takes part in virion assembly and budding, the data on the effect of potential antiviral agents on ETM localization and structure in the lipid environment may provide a basis for further studies of potential coronavirus E-protein inhibitors.

Nanoparticles are produced in natural phenomena or synthesized artificially for technological applications. Their frequent contact with humans has been judged potentially harmful for health, and numerous studies are ongoing to understand the mechanisms of the toxicity of nanoparticles. At the macroscopic level, the toxicity can be established in vitro or in vivo by measuring the survival of cells. At the sub-microscopic level, scientists want to unveil the molecular mechanisms of the first interactions of nanoparticles with cells via the cell membrane, before the toxicity cascades within the whole cell. Unveiling a molecular understanding of the nanoparticle-membrane interface is a tricky challenge, because of the chemical complexity of this system and its nanosized dimensions buried within bulk macroscopic environments. In this review, we highlight how, in the last 10 years, second-order nonlinear optical (NLO) spectroscopy, and specifically vibrational sum frequency generation (SFG), has provided a new understanding of the structural, physicochemical, and dynamic properties of these biological interfaces, with molecular sensitivity. We will show how the intrinsic interfacial sensitivity of second-order NLO and the chemical information of vibrational SFG spectroscopy have revealed new knowledge of the molecular mechanisms that drive nanoparticles to interact with cell membranes, from both sides, the nanoparticles and the membrane properties.

In recent years, there has been a heightened interest in the self-assembly of nanoparticles (NPs) that is mediated by their adsorption onto lipid membranes. The interplay between the adhesive energy of NPs on a lipid membrane and the membrane\'s curvature energy causes it to wrap around the NPs. This results in an interesting membrane curvature-mediated interaction, which can lead to the self-assembly of NPs on lipid membranes. Recent studies have demonstrated that Janus spherical NPs, which adhere to lipid vesicles, can self-assemble into well-ordered nanoclusters with various geometries, including a few Platonic solids. The present study explores the additional effect of geometric anisotropy on the self-assembly of Janus NPs on lipid vesicles. Specifically, the current study utilized extensive molecular dynamics simulations to investigate the arrangement of Janus spherocylindrical NPs on lipid vesicles. We found that the additional geometric anisotropy significantly expands the range of NPs\' self-assemblies on lipid vesicles. The specific geometries of the resulting nanoclusters depend on several factors, including the number of Janus spherocylindrical NPs adhering to the vesicle and their aspect ratio. The lipid membrane-mediated self-assembly of NPs, demonstrated by this work, provides an alternative cost-effective route for fabricating highly engineered nanoclusters in three dimensions. Such structures, with the current wide range of material choices, have great potential for advanced applications, including biosensing, bioimaging, drug delivery, nanomechanics, and nanophotonics.

Antimicrobial peptides (AMPs) are increasingly recognized as potent therapeutic agents, with their selective affinity for pathological membranes, low toxicity profile, and minimal resistance development making them particularly attractive in the pharmaceutical landscape. This study offers a comprehensive analysis of the interaction between specific AMPs, including magainin-2, pleurocidin, CM15, LL37, and clavanin, with lipid bilayer models of very different compositions that have been ordinarily used as biological membrane models of healthy mammal, cancerous, and bacterial cells. Employing unbiased molecular dynamics simulations and metadynamics techniques, we have deciphered the intricate mechanisms by which these peptides recognize pathogenic and pathologic lipid patterns and integrate into lipid assemblies. Our findings reveal that the transverse component of the peptide\'s hydrophobic dipole moment is critical for membrane interaction, decisively influencing the molecule\'s orientation and expected therapeutic efficacy. Our approach also provides insight on the kinetic and dynamic dependence on the peptide orientation in the axial and azimuthal angles when coming close to the membrane. The aim is to establish a robust framework for the rational design of peptide-based, membrane-targeted therapies, as well as effective quantitative descriptors that can facilitate the automated design of novel AMPs for these therapies using machine learning methods.

We investigated the impacts of spherical and triangular-plate-shaped lipid-coated silver nanoparticles (AgNPs) designed to prevent surface oxidation and silver ion (Ag+) dissolution in a small-scale microcosm to examine the role of shape and surface functionalization on biological interactions. Exposures were conducted in microcosms consisting of algae, bacteria, crustaceans, and fish embryos. Each microcosm was exposed to one of five surface chemistries within each shape profile (at 0, 0.1, or 0.5 mg Ag/L) to investigate the role of shape and surface composition on organismal uptake and toxicity. The hybrid lipid-coated AgNPs did not result in any significant release of Ag+ and had the most significant toxicity to D. magna, the most sensitive species, although the bacterial population growth rate was reduced in all exposures. Despite AgNPs resulting in increasing algal growth over the experiment, we found no correlation between algal growth and the survival of D. magna, suggesting that the impacts of the AgNPs on bacterial survival influenced algal growth rates. No significant impacts on zebrafish embryos were noted in any exposure. Our results demonstrate that the size, shape, and surface chemistry of AgNPs can be engineered to achieve specific goals while mitigating nanoparticle risks.

Trehalose is widely acknowledged for its ability to stabilize plasma membranes during dehydration. However, the exact mechanism by which trehalose interacts with lipid bilayers remains presently unclear. In this study, we conducted atomistic molecular dynamic simulations on asymmetric model bilayers that mimic the membrane of human red blood cells at various trehalose and water contents. We considered three different hydration levels mimicking the full hydration to desiccation scenarios. Results indicate that the asymmetric distribution of lipids did not significantly influence the computed structural characteristics at full and low hydration. At dehydration, however, the order parameter obtained from the symmetric bilayer is significantly higher compared to those obtained from asymmetric ones. Analysis of hydrogen bonds revealed that the protective ability of trehalose is well described by the water replacement hypothesis at full and low hydration, while at dehydration other interaction mechanisms associated with trehalose exclusion from the bilayer may involve. In addition, we found that trehalose exclusion is not attributed to sugar saturation but rather to the reduction in hydration levels. It can be concluded that the protective effect of trehalose is not only related to the hydration level of the bilayer, but also closely tied to the asymmetric distribution of lipids within each leaflet.

Understanding and manipulating the interactions between foreign bodies and cell membranes during endo- and phagocytosis is of paramount importance, not only for the fate of living cells but also for numerous biomedical applications. This study aims to elucidate the role of variables such as anisotropic particle shape, curvature, orientation, membrane tension, and adhesive strength in this essential process using a minimal experimental biomimetic system comprising giant unilamellar vesicles and rod-like particles with different curvatures and aspect ratios. We find that the particle wrapping process is dictated by the balance between the elastic free energy penalty and adhesion free energy gain, leading to two distinct engulfment pathways, tip-first and side-first, emphasizing the significance of the particle orientation in determining the pathway. Moreover, our experimental results are consistent with theoretical predictions in a state diagram, showcasing how to control the wrapping pathway from surfing to partial to complete wrapping by the interplay between membrane tension and adhesive strength. At moderate particle concentrations, we observed the formation of rod clusters, which exhibited cooperative and sequential wrapping. Our study contributes to a comprehensive understanding of the mechanistic intricacies of endocytosis by highlighting how the interplay between the anisotropic particle shape, curvature, orientation, membrane tension, and adhesive strength can influence the engulfment pathway.

The oral bioavailability of therapeutic peptides is generally low. To increase peptide transport across the gastrointestinal barrier, permeation enhancers are often used. Despite their widespread use, mechanistic knowledge of permeation enhancers is limited. To address this, we here investigate the interactions of six commonly used permeation enhancers with lipid membranes in simulated intestinal environments. Specifically, we study the interactions of the permeation enhancers sodium caprate, dodecyl maltoside, sodium cholate, sodium dodecyl sulfate, melittin, and penetratin with epithelial cell-like model membranes. To mimic the molecular composition of the real intestinal environment, the experiments are performed with two peptide drugs, salmon calcitonin and desB30 insulin, in fasted-state simulated intestinal fluid. Besides providing a comparison of the membrane interactions of the studied permeation enhancers, our results demonstrate that peptide drugs as well as intestinal-fluid components may substantially change the membrane activity of permeation enhancers. This highlights the importance of testing permeation enhancement in realistic physiological environments and carefully choosing a permeation enhancer for each individual peptide drug.