How molecular architecture defines quantum yields.

Understanding the intricate relationship between molecular architecture and function underpins most challenges at the forefront of chemical innovation. Bond-forming reactions are particularly influenced by the topology of a chemical structure, both on small molecule scale and in larger macromolecular frameworks. Herein, we elucidate the impact that molecular architecture has on the photo-induced cyclisations of a series of monodisperse macromolecules with defined spacers between photodimerisable moieties, and examine the relationship between propensity for intramolecular cyclisation and intermolecular network formation. We demonstrate a goldilocks zone of maximum reactivity between the sterically hindered and entropically limited regimes with a quantum yield of intramolecular cyclisation that is nearly an order of magnitude higher than the lowest value. As a result of the molecular design of trifunctional macromolecules, their quantum yields can be deconvoluted into the formation of two different cyclic isomers, as rationalised with molecular dynamics simulations. Critically, we visualise our solution-based studies with light-based additive manufacturing. We formulate four photoresists for microprinting, revealing that the precise positioning of functional groups is critical for resist performance, with lower intramolecular quantum yields leading to higher-quality printing in most cases.

The concentration-dependent effect of hydrocortisone on the structure of model lung surfactant monolayer by using an in silico approach.

Understanding the adsorption mechanism of corticosteroids in the lung surfactant requires the knowledge of corticosteroid molecular interactions with lung surfactant monolayer (LSM). We employed coarse-grained molecular dynamics simulation to explore the action of hydrocortisone on an LSM comprised of a phospholipid, cholesterol and surfactant protein. The structural and dynamical morphology of the lung surfactant monolayer at different surface tensions were investigated to assess the monolayer compressibility. The simulations were also conducted at the two extreme ends of breathing cycles: exhalation (0 mN m-1 surface tension) and inhalation (20 mN m-1 surface tension). The impact of surface tension and hydrocortisone concentration on the monolayer compressibility and stability are significant, resulting the monolayer expansion at higher surface tension. However, at low surface tension, the highly compressed monolayer induces monolayer instability in the presence of the drug due to the accumulation of surfactant protein and drug. The constant area per lipid simulation results demonstrate that the surface pressure-area isotherms show a decrease in area-per-lipid with increased drug concentration. The drug-induced expansion causes considerable instability in the monolayer after a specific drug concentration is attained at inhalation breathing condition, whereas, for exhalation breathing, the monolayer gets more compressed, causing the LSM to collapse. The monolayer collapse occurs for inhalation due to the higher drug concentration, whereas for exhalation due to the accumulation of surfactant proteins and drugs. The findings from this study will aid in enhancing the knowledge of molecular interactions of corticosteroid drugs with lung surfactants to treat respiratory diseases.

The role of ion-lipid interactions and lipid packing in transient defects caused by phenolic compounds.

The transient disruption of membranes for the passive permeation of ions or small molecules is a complex process relevant to understanding physiological processes and biotechnology applications. Phenolic compounds are widely studied for their antioxidant and antimicrobial properties, and some of these activities are based on the interactions of the phenolic compound with membranes. Ions are ubiquitous in cells and are known to alter the structure of phospholipid bilayers. Yet, ion-lipid interactions are usually ignored when studying the membrane-altering properties of phenolic compounds. This study aims to assess the role of Ca2+ ions on the membrane-disrupting activity of two phenolic acids and to highlight the role of local changes in lipid packing in forming transient defects or pores. Results from tethered bilayer lipid membrane electrical impedance spectroscopy experiments showed that Ca2+ significantly reduces membrane disruption by caffeic acid methyl ester and caffeic acid. As phenolic acids are known metal chelators, we used UV-vis and fluorescence spectroscopy to exclude the possibility that Ca2+ interferes with membrane disruption by binding to the phenolic compound and subsequently preventing membrane binding. Molecular dynamics simulations showed that Ca2+ but not caffeic acid methyl ester or caffeic acid increases lipid packing in POPC bilayers. The combined data confirm that Ca2+ reduces the membrane-disrupting activity of the phenolic compounds, and that Ca2+-induced changes to lipid packing govern this effect. We discuss our data in the context of ion-induced pores and transient defects and how lipid packing affects membrane disruption by small molecules.

Molecular basis of transport of surface functionalised gold nanoparticles to pulmonary surfactant.

Ligands like alkanethiol (e.g. dodecanethiol, hexadecanethiol, etc.) and polymers (e.g. poly(vinyl pyrrolidone), polyethylene glycol-thiol) capped to the gold nanoparticles (AuNPs) are widely used in biomedical field as drug carriers and as promising materials for probing and manipulating cellular processes. Ligand functionalised AuNPs are known to interact with the pulmonary surfactant (PS) monolayer once reaching the alveolar region. Therefore, it is crucial to understand the interaction between AuNPs and PS monolayers. Using coarse-grained molecular dynamics simulations, the effect of ligand density, and ligand length have been studied for two classes of ligands on a PS model monolayer consisting of DPPC, POPG, cholesterol and SP-B (mini-peptide). The ligands considered in this study are alkanethiol and polyethylene glycol (PEG) thiol as examples of hydrophobic and hydrophilic ligands, respectively. It was observed that the interaction between AuNPs and PS changes the biophysical properties of PS monolayer in compressed and expanded states. The AuNPs with hydrophilic ligand, can penetrate through the monolayer more easily, while the AuNPs with hydrophobic ligand are embedded in the monolayer and participated in deforming the monolayer structure particularly the monolayer in the compressed state. The bare AuNPs hinder to lower the monolayer surface tension value at the interface, however introducing ligand to the bare AuNPs or increasing the ligand length and density have an impact of lowering of monolayer surface tension to a minor extent. The simulation results guide the design of ligand protected NPs as drug carriers and can identify the nanoparticles' potential side effects on lung surfactant.

The Impact of Chromate on Pseudomonas aeruginosa Molybdenum Homeostasis.

Acquisition of the trace-element molybdenum via the high-affinity ATP-binding cassette permease ModABC is essential for Pseudomonas aeruginosa respiration in anaerobic and microaerophilic environments. This study determined the X-ray crystal structures of the molybdenum-recruiting solute-binding protein ModA from P. aeruginosa PAO1 in the metal-free state and bound to the group 6 metal oxyanions molybdate, tungstate, and chromate. Pseudomonas aeruginosa PAO1 ModA has a non-contiguous dual-hinged bilobal structure with a single metal-binding site positioned between the two domains. Metal binding results in a 22° relative rotation of the two lobes with the oxyanions coordinated by four residues, that contribute six hydrogen bonds, distinct from ModA orthologues that feature an additional oxyanion-binding residue. Analysis of 485 Pseudomonas ModA sequences revealed conservation of the metal-binding residues and ß-sheet structural elements, highlighting their contribution to protein structure and function. Despite the capacity of ModA to bind chromate, deletion of modA did not affect P. aeruginosa PAO1 sensitivity to chromate toxicity nor impact cellular accumulation of chromate. Exposure to sub-inhibitory concentrations of chromate broadly perturbed P. aeruginosa metal homeostasis and, unexpectedly, was associated with an increase in ModA-mediated molybdenum uptake. Elemental analyses of the proteome from anaerobically grown P. aeruginosa revealed that, despite the increase in cellular molybdenum upon chromate exposure, distribution of the metal within the proteome was substantially perturbed. This suggested that molybdoprotein cofactor acquisition may be disrupted, consistent with the potent toxicity of chromate under anaerobic conditions. Collectively, these data reveal a complex relationship between chromate toxicity, molybdenum homeostasis and anaerobic respiration.

Is the SARS CoV-2 Omicron Variant Deadlier and More Transmissible Than Delta Variant?

Genetic variants of severe acute respiratory syndrome coronavirus (SARS-CoV-2) have been globally surging and devastating many countries around the world. There are at least eleven reported variants dedicated with inevitably catastrophic consequences. In 2021, the most dominant Delta and Omicron variants were estimated to lead to more severity and deaths than other variants. Furthermore, these variants have some contagious characteristics involving high transmissibility, more severe illness, and an increased mortality rate. All outbreaks caused by the Delta variant have been rapidly skyrocketing in infection cases in communities despite tough restrictions in 2021. Apart from it, the United States, the United Kingdom and other high-rate vaccination rollout countries are still wrestling with this trend because the Delta variant can result in a significant number of breakthrough infections. However, the pandemic has changed since the latest SARS-CoV-2 variant in late 2021 in South Africa, Omicron. The preliminary data suggest that the Omicron variant possesses 100-fold greater than the Delta variant in transmissibility. Therefore, this paper aims to review these characteristics based on the available meta-data and information from the first emergence to recent days. Australia and the five most affected countries, including the United States, India, Brazil, France, as well as the United Kingdom, are selected in order to review the transmissibility, severity and fatality due to Delta and Omicron variants. Finally, the vaccination programs for each country are also reviewed as the main factor in prevention.

Concentration-Dependent Effect of the Steroid Drug Prednisolone on a Lung Surfactant Monolayer.

The lung surfactant monolayer (LSM) is the main barrier for particles entering the lung, including steroid drugs used to treat lung diseases. The present study combines Langmuir experiments and coarse-grained (CG) molecular dynamics simulations to investigate the concentration-dependent effect of steroid drug prednisolone on the structure and morphology of a model LSM. The surface pressure-area isotherms for the Langmuir monolayers reveal a concentration-dependent decrease in area per lipid (APL). Results from simulations at a fixed surface tension, representing inhalation and exhalation conditions, suggest that at high drug concentrations, prednisolone induces a collapse of the LSM, which is likely caused by the inability of the drug to diffuse into the bilayer. Overall, the monolayer is most susceptible to drug-induced collapse at surface tensions representing exhalation conditions. The presence of cholesterol also exacerbates the instability. The findings of this investigation might be helpful for better understanding the interaction between steroid drug prednisolone and lung surfactants in relation to off-target effects.

Structural and biochemical characterization of Acinetobacter baumannii ZnuA.

Acinetobacter baumannii is a Gram-negative nosocomial pathogen associated with significant disease. Crucial to the survival and pathogenesis of A. baumannii is the ability to acquire essential micronutrients such as Zn(II). Recruitment of Zn(II) by A. baumannii is mediated, at least in part, by the periplasmic solute-binding protein ZnuA and the ATP-binding cassette transporter ZnuBC. Here, we combined genomic, biochemical, and structural approaches to characterize A. baumannii AB5075_UW ZnuA. Bioinformatic analyses using a diverse collection of A. baumannii genomes determined that ZnuA is highly conserved, with the binding site comprised by three strictly conserved histidine residues. The structure of metal-free ZnuA was determined at 2.1 Å resolution, with molecular dynamics analyses revealing loop α2ß2, which harbors the putative Zn(II)-coordinating residue His41, to be highly mobile in the metal-free state. The contribution of the putative binding site histidine residues to Zn(II) interaction was further probed by mutagenesis. Analysis of ZnuA mutant variants was performed by quantitative metal binding assays, differential scanning fluorimetry, and affinity measurements, which showed that all three histidine residues contributed to Zn(II)-recruitment, albeit to different extents. Collectively, these analyses provide insight into the mechanism of Zn(II)-binding by A. baumannii ZnuA and expand our understanding of the functional diversity of Zn(II)-recruiting proteins.

Drug Meets Monolayer: Understanding the Interactions of Sterol Drugs with Models of the Lung Surfactant Monolayer Using Molecular Dynamics Simulations.

The lung surfactant monolayer (LSM) is a thin layer of lipids and proteins that forms the air/water interface of the alveoli. The primary function of the LSM is to reduce the surface tension at the air/water interface during breathing. The LSM also forms the main biological barrier for any inhaled particles, including drugs, to treat lung diseases. Elucidating the mechanism by which these drugs bind to and absorb into the LSM requires a molecular-level understanding of any drug-induced changes to the morphology, structure, and phase changes of the LSM.Molecular dynamics simulations have been used extensively to study the structure and dynamics of the LSM. The monolayer is usually simulated in at least two states: the compressed state, mimicking exhalation, and the expanded state, mimicking inhalation. In this chapter, we provide detailed instructions on how to set up, run, and analyze coarse-grained MD simulations to study the concentration-dependent effect of a sterol drug on the LSM, both in the expanded and compressed state.

The steroid mometasone alters protein containing lung surfactant monolayers in a concentration-dependent manner.

Mometasone is an investigational anti-inflammatory steroidal drug to treat inflammation via pulmonary administration. For steroid drugs to be effective they need to be adsorbed by lung surfactants, a thin monolayer at the air-water interface in alveoli that reduces surface tension. Information on the molecular-level interactions of the drug with lung surfactants is useful to understand the mechanism of adsorption. In this study, we use coarse-grained molecular dynamics simulation to understand the concentration-dependent effect of mometasone on a lung surfactant monolayer (LSM) composed of lipids and surfactant proteins, under two different breathing conditions (exhalation, at surface tension 0 mNm-1 and inhalation, surface tension 20-25 mNm-1). A series of fixed-APL and fixed-surface tension simulations were used to demonstrate that in the absence of drugs, the model LSM reproduces the surface tensions for the compressed and expanded states, as well as compressibility at different surface tensions. In-depth analysis of simulations of a LSM in the presence of five different drug concentrations shows that mometasone alters the structure and dynamics of the LSM in a concentration-dependent manner. Mometasone induces a collapse in the monolayer that is affected by the surfactant protein and surface tension. Overall, these findings suggest that the surfactant proteins, surface tension and drug concentration are all critical components affecting monolayer stability and drug adsorption. The outcomes of this study may be beneficial for a more in-depth understanding of how mometasone is adsorbed by lung surfactants.

Phenolic compounds alter the ion permeability of phospholipid bilayers via specific lipid interactions.

This study aims to understand the role of specific phenolic-lipid interactions in the membrane-altering properties of phenolic compounds. We combine tethered lipid bilayer (tBLM) electrical impedance spectroscopy (EIS) with all-atom molecular dynamics (MD) simulations to study the membrane interactions of six phenolic compounds: caffeic acid methyl ester, caffeic acid, 3,4 dihydroxybenzoic acid, chlorogenic acid, syringic acid and p-coumaric acid. tBLM/EIS experiments showed that caffeic acid methyl ester, caffeic acid and 3,4 dihydroxybenzoic acid significantly increase the permeability of phospholipid bilayers to Na+ ions. In contrast, chlorogenic acid, syringic acid and p-coumaric acid showed no effect. Experiments with lipids lacking the phosphate group show a significant decrease in the membrane-altering effects indicating that specific phenolic-lipid interactions are critical in altering ion permeability. MD simulations confirm that compounds that alter ion permeability form stable interactions with the phosphate oxygen. In contrast, inactive phenolic compounds are superficially bound to the membrane surface and primarily interact with interfacial water. Our combined results show that compounds with similar structures can have very different effects on ion permeability in membranes. These effects are governed by specific interactions at the water-lipid interface and show no correlation with lipophilicity. Furthermore, none of the compounds alter the overall structure of the phospholipid bilayer as determined by area per lipid and order parameters. Based on data from this study and previous findings, we propose that phenolic compounds can alter membrane ion permeability by causing local changes in lipid packing that subsequently reduce the energy barrier for ion-induced pores.

Shape matters-the interaction of gold nanoparticles with model lung surfactant monolayers.

The lung surfactant monolayer (LSM) forms the main biological barrier for any inhaled particles to enter our bloodstream, including gold nanoparticles (AuNPs) present as air pollutants and under investigation for use in biomedical applications. Understanding the interaction of AuNPs with lung surfactant can assist in understanding how AuNPs enter our lungs. In this study, we use coarse-grained molecular dynamics simulations to investigate the effect of four different shape D AuNPs (spherical, box, icosahedron and rod) on the structure and dynamics of a model LSM, with a particular focus on differences resulting from the shape of the AuNP. Monolayer-AuNP systems were simulated in two different states: the compressed state and the expanded state, representing inhalation and exhalation conditions, respectively. Our results indicate that the compressed state is more affected by the presence of the AuNPs than the expanded state. Our results show that in the compressed state, the AuNPs prevent the monolayer from reaching the close to zero surface tension required for normal exhalation. In the compressed state, all four nanoparticles (NPs) reduce the lipid order parameters and cause a thinning of the monolayer where the particles drag surfactant molecules into the water phase. Comparing the different properties shows no trend concerning which shape has the biggest effect on the monolayer, as shape-dependent effects vary among the different properties. Insights from this study might assist future work of how AuNP shapes affect the LSM during inhalation or exhalation conditions.

Polydisperse Aerosol Transport and Deposition in Upper Airways of Age-Specific Lung.

A comprehensive understanding of airflow characteristics and particle transport in the human lung can be useful in modelling to inform clinical diagnosis, treatment, and management, including prescription medication and risk assessment for rehabilitation. One of the difficulties in clinical treatment of lung disorders lies in the patients' variable physical lung characteristics caused by age, amongst other factors, such as different lung sizes. A precise understanding of the comparison between different age groups with various flow rates is missing in the literature, and this study aims to analyse the airflow and aerosol transport within the age-specific lung. ANSYS Fluent solver and the large-eddy simulation (LES) model were employed for the numerical simulation. The numerical model was validated with the available literature and the computational results showed airway size-reduction significantly affected airflow and particle transport in the upper airways. This study reports higher deposition at the mouth-throat region for larger diameter particles. The overall deposition efficiency (DE) increased with airway size reduction and flow rate. Lung aging effected the pressure distribution and a higher pressure drop was reported for the aged lung as compared to the younger lung. These findings could inform medical management through individualised simulation of drug-aerosol delivery processes for the patient-specific lung.

Computational Studies of Lipid-Wrapped Gold Nanoparticle Transport Through Model Lung Surfactant Monolayers.

Colloidal nanoparticles, such as gold nanoparticles (AuNPs), are promising materials for the delivery of hydrophilic drugs via the pulmonary route. The inhaled nanoparticle drug carriers primarily deposit in lung alveoli and interact with the alveolar surface known as lung surfactants. Therefore, it is vital to understand the interactions of nanocarriers with the surfactant layer. To understand the interactions at the molecular level, here we simulated model lung surfactant monolayers with phospholipid (PL)-wrapped AuNPs at the vacuum-water interface using coarse-grained molecular dynamics simulations. The PL-wrapped AuNPs quickly adsorbed into the surfactant layer, altered the structural properties of the monolayer, and at high concentrations initiated the compressed monolayer to collapse/buckle. Among the surfactant monolayer lipid components, cholesterol adsorbed to the AuNPs preferentially over PL species. The position of the adsorbed PL-AuNPs within the monolayer, and subsequent monolayer perturbation, vary depending on the monolayer phase, monolayer composition, and species of PL used as a ligand. Information provided by these molecular dynamic simulations helps to rationalize why some colloidal nanoparticles work better as nanocarriers than others and aid the design of new ones, to avoid biological toxicity and improve efficacy for pulmonary drug delivery.

The role of SP-B1-25 peptides in lung surfactant monolayers exposed to gold nanoparticles.

Lung surfactant (LS) monolayers that continuously expand and compress during breathing cycles, act as the first line barrier for inhaled nanoparticles. It is known that nanoparticles which adsorb to the surface of the surfactant layer facilitate the rearrangement of lipids and peptides at various stages of the breathing cycle. However, the structural mechanisms for this ability of the lipid rearrangement are not yet fully understood. Coarse-grained molecular dynamics simulations are performed to investigate the role of surfactant protein B (SP-B) segments (SP-B1-25) in modulating the biophysical properties of the surfactant monolayer in the presence of polydisperse gold nanoparticles (AuNPs) at different concentrations. Herein, we observe that the AuNPs significantly alter the inherent structural and dynamical properties of the monolayer and its components in three different breathing states. When adsorbed into the monolayer, the AuNPs inhibit the ability of the monolayer to recover its surface tension and other properties. The presence of SP-B1-25 in the monolayer accelerates the diffusion of the monolayer phospholipids, contrarily to the role of AuNPs on phospholipid diffusion. Also, the AuNPs and the peptides in the monolayer significantly increase their agglomeration in the presence of one another. Overall, the simulations predict that the presence of polydisperse AuNPs hampers the stability and biophysical functions of the LS in contrast to the role of the peptide. This study provides a clear view of the hydrophobic peptide role in the LS monolayer at the interface along with the interactions and the translocation of AuNPs that could have a significant impact to assess the NPs inhalation.

Molecular insights on the interference of simplified lung surfactant models by gold nanoparticle pollutants.

Inhaled nanoparticles (NPs) are experienced by the first biological barrier inside the alveolus known as lung surfactant (LS), a surface tension reducing agent, consisting of phospholipids and proteins in the form of the monolayer at the air-water interface. The monolayer surface tension is continuously regulated by the alveolus compression and expansion and protects the alveoli from collapsing. Inhaled NPs can reach deep into the lungs and interfere with the biophysical properties of the lung components. The interaction mechanisms of bare gold nanoparticles (AuNPs) with the LS monolayer and the consequences of the interactions on lung function are not well understood. Coarse-grained molecular dynamics simulations were carried out to elucidate the interactions of AuNPs with simplified LS monolayers at the nanoscale. It was observed that the interactions of AuNPs and LS components deform the monolayer structure, change the biophysical properties of LS and create pores in the monolayer, which all interfere with the normal lungs function. The results also indicate that AuNP concentrations >0.1 mol% (of AuNPs/lipids) hinder the lowering of the LS surface tension, a prerequisite of the normal breathing process. Overall, these findings could help to identify the possible consequences of airborne NPs inhalation and their contribution to the potential development of various lung diseases.