Single Atom Engineered Antibiotics Overcome Bacterial Resistance.

The outbreak of antibiotic-resistant bacteria, or "superbugs", poses a global public health hazard due to their resilience against the most effective last-line antibiotics. Identifying potent antibacterial agents capable of evading bacterial resistance mechanisms represents the ultimate defense strategy. This study shows that -the otherwise essential micronutrient- manganese turns into a broad-spectrum potent antibiotic when coordinated with a carboxylated nitrogen-doped graphene.

Mechanistic insights into interactions between ionizable lipid nanodroplets and biomembranes.

Delivery of RNA into cells using lipid nanoparticles (LNPs) has been a significant breakthrough in RNA-based medicine, with clinical applicability expanded through the use of ionizable lipids (ILs). These unique lipids can alter their charge state in response to pH changes, which is crucial for pH-triggered endosomal escape and effective lipid-mediated RNA delivery. In this study, we conducted a comprehensive set of molecular dynamics (MD) simulations to investigate interactions between IL-containing lipid nanodroplets (LNDs) and cell membrane models.

Stacked or Folded? Impact of Chelate Cooperativity on the Self-Assembly Pathway to Helical Nanotubes from Dinucleobase Monomers.

Self-assembled nanotubes exhibit impressive biological functions that have always inspired supramolecular scientists in their efforts to develop strategies to build such structures from small molecules through a bottom-up approach. One of these strategies employs molecules endowed with self-recognizing motifs at the edges, which can undergo either cyclization-stacking or folding-polymerization processes that lead to tubular architectures. Which of these self-assembly pathways is ultimately selected by these molecules is, however, often difficult to predict and even to evaluate experimentally.

Atomistic Insights into Organization of RNA-Loaded Lipid Nanoparticles.

RNA-based therapies have shown promise in a wide range of applications, from cancer therapy, treatment of inherited diseases to vaccination. Encapsulation of RNA into ionizable lipid (IL) containing lipid nanoparticles (LNPs) has enabled its safe and targeted delivery. We present here the simulations of the self-assembly process of pH-sensitive RNA-carrying LNPs and their internal morphology.

Multiscale Modeling Unravels the Influence of Biomembranes on the Photochemical Properties of Embedded Anti-Oxidative Polyphenolic and Phenanthroline Chelating Dyes.

The embedding of caffeate methyl ester, the flavonoids luteolin and quercetin, and the -phenanthroline and neocuproine in a liquid disordered lipid bilayer has been studied through extensive atomistic calculations. The location and the orientation of these bio-active antioxidants are explained and analyzed. While the two phenanthrolines strongly associate with the lipid tail region, the other three compounds are rather found among the head groups.

Computer Aided Development of Nucleic Acid Applications in Nanotechnologies.

Utilization of nucleic acids (NAs) in nanotechnologies and nanotechnology-related applications is a growing field with broad application potential, ranging from biosensing up to targeted cell delivery. Computer simulations are useful techniques that can aid design and speed up development in this field. This review focuses on computer simulations of hybrid nanomaterials composed of NAs and other components.

Self-Assembly of Chiro-Optical Materials from Nonchiral Oligothiophene-Porphyrin Derivatives and Random Coil Synthetic Peptides.

Biomimetic chiral optoelectronic materials can be utilized in electronic devices, biosensors and artificial enzymes. Herein, this work reports the chiro-optical properties and architectural arrangement of optoelectronic materials generated from self-assembly of initially nonchiral oligothiophene-porphyrin derivatives and random coil synthetic peptides. The photo-physical- and structural properties of the materials were assessed by absorption-, fluorescence- and circular dichroism spectroscopy, as well as dynamic light scattering, scanning electron microscopy and theoretical calculations.

Role of Ionizable Lipids in SARS-CoV-2 Vaccines As Revealed by Molecular Dynamics Simulations: From Membrane Structure to Interaction with mRNA Fragments.

Recent advances in RNA-based medicine have provided new opportunities for the global current challenge, i.e., the COVID-19 pandemic.

Carbon Dots Detect Water-to-Ice Phase Transition and Act as Alcohol Sensors Fluorescence Turn-Off/On Mechanism.

Highly fluorescent carbon nanoparticles called carbon dots (CDs) have been the focus of intense research due to their simple chemical synthesis, nontoxic nature, and broad application potential including optoelectronics, photocatalysis, biomedicine, and energy-related technologies. Although a detailed elucidation of the mechanism of their photoluminescence (PL) remains an unmet challenge, the CDs exhibit robust, reproducible, and environment-sensitive PL signals, enabling us to monitor selected chemical phenomena including phase transitions or detection of ultralow concentrations of molecular species in solution. Herein, we report the PL turn-off/on behavior of aqueous CDs allowing the reversible monitoring of the water-ice phase transition.

Influence of Membrane Phase on the Optical Properties of DPH.

The fluorescent molecule diphenylhexatriene (DPH) has been often used in combination with fluorescence anisotropy measurements, yet little is known regarding the non-linear optical properties. In the current work, we focus on them and extend the application to fluorescence, while paying attention to the conformational versatility of DPH when it is embedded in different membrane phases. Extensive hybrid quantum mechanics/molecular mechanics calculations were performed to investigate the influence of the phase- and temperature-dependent lipid environment on the probe.

Molecular Fluorophores Self-Organize into C-Dot Seeds and Incorporate into C-Dot Structures.

Various molecular fluorophores have been identified to be present during carbon-dot (C-dot) syntheses. However, the organization of such fluorophores in C-dots is still unknown. We study the self-assembly of 5-oxo-1,2,3,5-tetrahydroimidazo-[1,2-α]-pyridine-7-carboxylic acid (IPCA), a molecular fluorophore present during the synthesis of C-dots from citric acid and ethylenediamine.

Cyanine dyes with tail length asymmetry enhance photoselection: A multiscale study on DiD probes in a liquid disordered membrane.

Visualization of membrane domains like lipid rafts in natural or artificial membranes is a crucial task for cell biology. For this purpose, fluorescence microscopy is often used. Since fluorescing probes in lipid membranes partition specifically in e.

Orientational distribution of DPH in lipid membranes: a comparison of molecular dynamics calculations and experimental time-resolved anisotropy experiments.

Characterization of the membrane phases is a crucial task in cell biology. Cells differ in composition of the lipids and consequently in adopted phases. The phases can be discriminated based upon lipid ordering and molecular diffusion and their identification could be used for characterization of cell membranes.

Dermal Delivery of Selected Polyphenols from Silybum marianum. Theoretical and Experimental Study.

Silymarin is a well-known standardized extract from the seeds of milk thistle ( L., Asteraceae) with a pleiotropic effect on human health, including skin anticancer potential. Detailed characterization of flavonolignans properties affecting interactions with human skin was of interest.

Membrane-attached mammalian cytochromes P450: An overview of the membrane's effects on structure, drug binding, and interactions with redox partners.

Mammalian cytochromes P450 are an important class of enzymes involved in the biotransformation of many endo- and exogenous compounds. Cytochrome P450 isoforms are attached to the membrane of the endoplasmic reticulum or mitochondria, and their catalytic domains move along the membrane surface while being partially immersed in the membrane environment. Their active sites are connected to both the membrane and cytosolic environments via a complex network of access channels.

Structural Dynamics of Carbon Dots in Water and N, N-Dimethylformamide Probed by All-Atom Molecular Dynamics Simulations.

Carbon dots (CDs), one of the youngest members of the carbon nanostructure family, are now widely experimentally studied for their tunable fluorescence properties, bleaching resistance, and biocompatibility. Their interaction with biomolecular systems has also been explored experimentally. However, many atomistic details still remain unresolved.

Molecular insights into the role of a distal F240A mutation that alters CYP1A1 activity towards persistent organic pollutants.

Background: Cytochromes P450 are major drug-metabolizing enzymes involved in the biotransformation of diverse xenobiotics and endogenous chemicals. Persistent organic pollutants (POPs) are toxic hydrophobic compounds that cause serious environmental problems because of their poor degradability. This calls for rational design of enzymes capable of catalyzing their biotransformation.

Effect of Lipid Charge on Membrane Immersion of Cytochrome P450 3A4.

Microsomal cytochrome P450 enzymes (CYPs) are membrane-attached enzymes that play indispensable roles in biotransformations of numerous endogenous and exogenous compounds. Although recent progress in experiments and simulations has allowed many important features of CYP-membrane interactions to be deciphered, many other aspects remain underexplored. Using microsecond-long molecular dynamics simulations, we analyzed interaction of CYP3A4 with bilayers composed of lipids differing in their polar head groups, i.

In silico pharmacology: Drug membrane partitioning and crossing.

Over the past decade, molecular dynamics (MD) simulations have become particularly powerful to rationalize drug insertion and partitioning in lipid bilayers. MD simulations efficiently support experimental evidences, with a comprehensive understanding of molecular interactions driving insertion and crossing. Prediction of drug partitioning is discussed with respect to drug families (anesthetics; β-blockers; non-steroidal anti-inflammatory drugs; antioxidants; antiviral drugs; antimicrobial peptides).

Role of Enzyme Flexibility in Ligand Access and Egress to Active Site: Bias-Exchange Metadynamics Study of 1,3,7-Trimethyluric Acid in Cytochrome P450 3A4.

Although the majority of enzymes have buried active sites, very little is known about the energetics and mechanisms associated with substrate and product channeling in and out. Gaining direct information about these processes is a challenging task both for experimental and theoretical techniques. Here, we present a methodology that enables following of a ligand during its passage to the active site of cytochrome P450 (CYP) 3A4 and mapping of the free energy associated with this process.

The Role of Protein-Protein and Protein-Membrane Interactions on P450 Function.

This symposium summary, sponsored by the ASPET, was held at Experimental Biology 2015 on March 29, 2015, in Boston, Massachusetts. The symposium focused on: 1) the interactions of cytochrome P450s (P450s) with their redox partners; and 2) the role of the lipid membrane in their orientation and stabilization. Two presentations discussed the interactions of P450s with NADPH-P450 reductase (CPR) and cytochrome b5.

Structural Changes in Ceramide Bilayers Rationalize Increased Permeation through Stratum Corneum Models with Shorter Acyl Tails.

Ceramides are indispensable constituents of the stratum corneum (SC), the uppermost impermeable layer of human skin. Ceramides with shorter (four- to eight-carbon acyl chains) fatty acid chains increase skin and model membrane permeability, while further shortening of the chain leads to increased resistance to penetration almost as good as that of ceramides from healthy skin (24 carbons long on average). Here we address the extent to which the atomistic CHARMM36 and coarse-grain MARTINI molecular dynamics (MD) simulations reflect the skin permeability data.

Synergism of antioxidant action of vitamins E, C and quercetin is related to formation of molecular associations in biomembranes.

Vitamins E, C and polyphenols (flavonoids and non-flavonoids) are major natural antioxidants capable of preventing damage generated by oxidative stress. Here we show the capacity of these antioxidants to form non-covalent association within lipid bilayers close to the membrane/cytosol interface. Antioxidant regeneration is significantly enhanced in these complexes.

Effect of cholesterol on the structure of membrane-attached cytochrome P450 3A4.

Cholesterol is a widely researched component of biological membranes that significantly influences membrane properties. Human cytochrome P450 3A4 (CYP3A4) is an important drug-metabolizing enzyme, wherein the catalytic domain is attached to a membrane by an N-terminal α-helical transmembrane anchor. We analyzed the behavior of CYP3A4 immersed in a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membrane with various amounts of cholesterol.