Interfacial structurization between triolein and water from pH and buffer ions.

HYPOTHESIS: Understanding and manipulating the oil/water interface is important across various industries, including food, pharmaceuticals, cosmetics, and detergents. Many of these processes occur under elevated pH conditions in buffer systems, where base-catalyzed hydrolysis of triglyceride ester bonds leads to amphiphilic reaction products such as fatty acids. EXPERIMENTS: Here, pH-triggered alterations of the triolein/water interface are analyzed in the presence of phosphate (PB) and tris(hydroxymethyl)aminomethane (TRIS). Ellipsometry at the liquid/liquid interface, tensiometry, and scanning small angle X-ray scattering are used to study the formation of structures at the oil/water interface. Confocal Raman microscopy, nuclear magnetic resonance spectroscopy, and in silico modeling analyze compositional changes in the interfacial region. FINDINGS: pH and buffer ions were discovered to significantly modify the triglyceride/water interface, contrary to the decane/water control. Decreasing interfacial tensions from 32.4 to 2.2 mN/m upon pH increase from 6.5 to 9.5 is seen with multilamellar interfacial layers forming at pH around 9.0 in the presence of TRIS. Oleic acid from triolein hydrolysis and its further interaction with TRIS is held responsible for this. The new understanding can guide the design of pH- and ion-responsive functional materials and optimize industrial processes involving triglyceride/water interfaces.

The Impact of Interdisciplinary, Gender and Geographic Distributions on the Citation Patterns of the Journal of Chemical Information and Modeling.

There has been a growing recognition of the need for diversity and inclusion in scientific fields. This trend is reflected in the Journal of Chemical Information and Modeling (JCIM), where there has been a gradual increase in the number of papers that embrace this diversity. In this viewpoint, we analyze the evolution of the profile of papers published in JCIM from 1996 to 2022 addressing three diversity criteria, namely interdisciplinarity, geographic and gender distributions, and their impact on citation patterns. We used natural language processing tools for the classification of main areas and gender, as well as metadata, to analyze a total of 7384 articles published in the categories of research articles, reviews, and brief reports. Our analyses reveal that the relative number of articles and citation patterns are similar across the main areas within the scope of JCIM, and international collaboration and publications encompassing two to three research areas attract more citations. The percentage of female authors has increased from 1996 (less than 20%) to 2022 (more than 32%), indicating a positive trend toward gender diversity in almost all geographic regions, although the percentage of publications by single female authors remains lower than 20%. Most JCIM citations come from Europe and the Americas, with a tendency for JCIM papers to cite articles from the same continent. Furthermore, there is a correlation between the gender of the authors, as JCIM manuscripts authored by females are more likely to be cited by other JCIM manuscripts authored by females.

Exploring the Molecular Dynamics of a Lipid-A Vesicle at the Atom Level: Morphology and Permeation Mechanism.

Lipid-A was previously shown to spontaneously aggregate into a vesicle via the hybrid particle field approach. We assess the validity of the proposed vesiculation mechanism by simulating the resulting lipid-A vesicle at the atom level. The spatial confinement imposed by the vesicle geometry on the conformation and packing of lipid-A induces significant heterogeneity of physical properties in the inner and outer leaflets. It also induces tighter molecular packing and lower acyl chain order compared to the lamellar arrangement. Around 5% of water molecules passively permeates the vesicle membrane inward and outward. The permeation is facilitated by interactions with water molecules that are transported across the membrane by a network of electrostatic interactions with the hydrogen bond donors/acceptors in the N-acetylglucosamine ring and upper region of the acyl chains of lipid-A. The permeation process takes place at low rates but still at higher frequencies than observed for the lamellar arrangement of lipid-A. These findings not only substantiate the proposed lipid-A vesiculation mechanism but also reveal the complex structural dynamics of an important nonlamellar arrangement of lipid-A.

Accelerating Lipid Flip-Flop at Low Concentrations: A General Mechanism for Membrane Binding Peptides.

We report a physicochemical investigation of the lipid transport properties of model lipid membranes in the presence of the antimicrobial peptide indolicidin through comparisons of experimental SANS/SAXS scattering techniques to fully atomistic molecular dynamics simulations. In agreement with the experiment, we show that upon peripheral binding of the peptides, even at low concentrations, lipid flip-flop dynamics is greatly accelerated. Computer modeling elucidates the interplay between structural changes and lipid dynamics induced by peptides and proposes a mechanism for the mode of action of antimicrobial peptides, assessing the major role of entropy for the catalysis of the flipping events. The mechanism introduced here is universal for all peptides with preferential peripheral binding to the membrane as it does not depend on the specific amino acid sequence.

Inhibition of 3-Hydroxykynurenine Transaminase from Aedes aegypti and Anopheles gambiae: A Mosquito-Specific Target to Combat the Transmission of Arboviruses.

Arboviral infections such as Zika, chikungunya, dengue, and yellow fever pose significant health problems globally. The population at risk is expanding with the geographical distribution of the main transmission vector of these viruses, the Aedes aegypti mosquito. The global spreading of this mosquito is driven by human migration, urbanization, climate change, and the ecological plasticity of the species. Currently, there are no specific treatments for Aedes-borne infections. One strategy to combat different mosquito-borne arboviruses is to design molecules that can specifically inhibit a critical host protein. We obtained the crystal structure of 3-hydroxykynurenine transaminase (AeHKT) from A. aegypti, an essential detoxification enzyme of the tryptophan metabolism pathway. Since AeHKT is found exclusively in mosquitoes, it provides the ideal molecular target for the development of inhibitors. Therefore, we determined and compared the free binding energy of the inhibitors 4-(2-aminophenyl)-4-oxobutyric acid (4OB) and sodium 4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoate (OXA) to AeHKT and AgHKT from Anopheles gambiae, the only crystal structure of this enzyme previously known. The cocrystallized inhibitor 4OB binds to AgHKT with K i of 300 µM. We showed that OXA binds to both AeHKT and AgHKT enzymes with binding energies 2-fold more favorable than the crystallographic inhibitor 4OB and displayed a 2-fold greater residence time τ upon binding to AeHKT than 4OB. These findings indicate that the 1,2,4-oxadiazole derivatives are inhibitors of the HKT enzyme not only from A. aegypti but also from A. gambiae.

The Effect of Surface Composition on the Selective Capture of Atmospheric CO2 by ZIF Nanoparticles: The Case of ZIF-8.

We performed theoretical studies of CO2 capture in atmospheric conditions by the zeolitic imidazolate framework-8 (ZIF-8) via classical Monte Carlo (MC) simulations with Metropolis sampling and classical molecular dynamics (MD) simulations in the NVT and NPT ensembles and different thermodynamic conditions. The ZIF-8 framework was described by varying unit cell dimensions in the presence of pure gases of CO2, N2, O2, Ar, and H2O steam as well as binary mixtures of CO2:N2 and CO2:H2O in s 1:1 concentration. Different chemical compositions of the framework surface was considered to provide an accurate treatment of charge and charge distribution in the nanoparticle. Hence, surface groups were represented as unsaturated zinc atom (Zn+2), 2-methylimidazole (mImH), and deprotonated 2-methylimidazole (mIm-). Force field reparameterization of the surface sites was required to reproduce the interactions of the gas molecules with the ZIF-8 surface consistent with quantum mechanics (QM) calculations and Born-Oppenheimer molecular dynamics (BOMD). It was observed that ZIF-8 selectively captures CO2 due to the negligible concentrations of N2, O2, Ar, and H2O. These molecules spontaneously migrate to the inner pores of the framework. At the surface, there is a competitive interaction between H2O, CO2, and N2, for the positively charged ZIF-8 nanoparticle with a large binding energy advantage for water molecules (on average -62, -15, and -8 kcal/mol respectively). For the neutral ZIF-8 nanoparticle, the water molecules dominate the interactions due to the occurrence of hydrogen bond with the imidazolate groups at the surface. Simulations of binary mixtures of CO2/water steam and CO2/N2 were performed to investigate binding competition between these molecules for the framework positively charged and neutral surfaces. It was found that water molecules drastically block the interaction between CO2 molecules and the framework surface, decreasing CO2 capture in the central pore, and CO2 molecules fully block the interaction between N2 molecules and the framework. These findings show that CO2 capture by ZIF-8 is possible in atmospheric environments only upon dehydration of the atmospheric gas. It further shows that ZIF-8 capture of CO2 from the atmospheric environment is dependent on thermodynamic conditions and can be increased by decreasing temperature and/or increasing pressure.

Surface Assessment via Grid Evaluation (SuAVE) for Every Surface Curvature and Cavity Shape.

The surface assessment via grid evaluation (SuAVE) software was developed to account for the effect of curvature in the calculations of structural properties of chemical interfaces regardless of the chemical composition, asymmetry, and level of atom coarseness. It employs differential geometry techniques, enabling the representation of chemical surfaces as fully differentiable. In this article, we present novel developments of SuAVE to treat closed surfaces and complex cavity shapes. These developments expand the repertoire of curvature-dependent analyses already available in the previous version of SuAVE (e.g., area per lipid, density profiles, membrane thickness, deuterium-order parameters, volume per lipid, and surface curvature angle) to include new functionalities applicable to soft matter (e.g., sphericity, average radius, principal moment of inertia, and roundness) and crystalline porous materials (e.g., pore diameter, internal void volume, total area, and the total void volume of the unit cell structure). SuAVE can accurately handle chemical systems with high and low atom density as demonstrated for two distinct chemical systems: the lipid A vesicle and a set of selected metal-organic frameworks. The SuAVE software v2.0 is fully parallel and benefits from a compiler that supports OpenMP. SuAVE is freely available from https://github.com/SuAVE-Software/source and https://www.biomatsite.net/.

Bias Amplification in Gender, Gender Identity, and Geographical Affiliation.

In the quest for greater equity in science, individual attitudes and institutional policies should also embrace greater diversity and inclusion of minority groups. This viewpoint calls for a broader definition of gender bias in STEM to include gender identity and for increased attention to the issue of bias amplification due to geographic affiliation in the field of computational chemistry and chemoinformatics. It briefly discusses some active interventions to tackle bias on gender, gender identity, and geographic affiliation in STEM.

The tug of war between Al3+ and Na+ for order-disorder transitions in lipid-A membranes.

Cations play a critical role in the stability and morphology of lipid-A aggregates by neutralizing, hydrating and cross-linking these glycolipid molecules. Monophosphorylated lipid-A is the major immunostimulatory principle in commercially available adjuvants containing Al3+ such as adjuvant system 04 (AS04). The antagonist/agonist immunomodulatory properties of lipid-A are associated with chemical variations (e.g. the number of acyl chains and phosphate groups) and their aggregate arrangements (e.g. lamellar, nonlamellar or mixed). Therefore, the identification of the active form of lipid-A can provide valuable guidance in the development of vaccine adjuvants capable of boosting the immune system with decreased reactogenicity. Although the effect of mono and divalent cations on the structural polymorphism and endotoxicity of LPS has been previously investigated, much less is known about the effect of trivalent cations. We have investigated the effect of NaCl and AlCl3 salt solutions on the structural dynamics and stability of mono and diphosphorylated lipid-A membranes via atomistic MD simulations. The Al3+ ion exerts two major effects on the structural dynamics of lipid-A membranes. It acts as an efficient cross-linker of mono or diphosphorylated lipid-A molecules, thus stabilizing the lamellar arrangement of these glycolipids. It also alters the lipid-A packing and membrane fluidity, inducing disorder → order structural transitions of the membrane. This effect is promptly reversed upon the addition of NaCl solution, which promotes a nearly threefold increase in the amount of water in the carbohydrate moiety of the Al3+-containing lipid-A membranes. The exchange dynamics and residence times of cation-coordinated water molecules in these membranes provide insights into the molecular mechanism for the Na+-induced transition from a densely packed ordered phase to a disordered one. Al3+ counter-ions favor ordered lamellar aggregates, which has been previously associated with the lack of endotoxic activity and cytokine-inducing action. The resulting microscopic understanding of the structure and dynamics of lipid-A aggregates in the presence of Al3+ and Na+ salts can provide valuable guidance in the development of vaccine adjuvants capable of boosting the immune system with decreased reactogenicity.

A second generation of 1,2,4-oxadiazole derivatives with enhanced solubility for inhibition of 3-hydroxykynurenine transaminase (HKT) from Aedes aegypti.

The most widely used method for the control of the Aedes aegypti mosquito population is the chemical control method. It represents a time- and cost-effective way to curb several diseases (e.g. dengue, Zika, chikungunya, yellow fever) through vector control. For this reason, the discovery of new compounds with a distinct mode of action from the available ones is essential in order to minimize the rise of insecticide resistance. Detoxification enzymes are an attractive target for the discovery of new insecticides. The kynurenine pathway is an important metabolic pathway, and it leads to the chemically stable xanthurenic acid, biosynthesized from 3-hydroxykynurenine, a precursor of reactive oxygen and nitrogen species, by the enzyme 3-hydroxykynurenine transaminase (HKT). Previously, we have reported the effectiveness of 1,2,4-oxadiazole derivatives acting as larvicides for A. aegypti and AeHKT inhibitors from in vitro and in silico studies. Here, we report the synthesis of new sodium 4-[3-(aryl)-1,2,4-oxadiazol-5-yl] propanoates and the cognate HKT-inhibitory activity. These new derivatives act as competitive inhibitors with IC50 values in the range of 42 to 339 µM. We further performed molecular docking simulations and QSAR analysis for the previously synthesized sodium 4-[3-(aryl)-1,2,4-oxadiazol-5-yl] butanoates reported earlier by our group and the data produced herein. Most of the 1,2,4-oxadiazole derivatives, including the canonical compounds for both series, showed a similar binding mode with HKT. The binding occurs similarly to the co-crystallized inhibitor via anchoring to Arg356 and positioning of the aromatic ring and its substituents outwards at the entry of the active site. QSAR analysis was performed in search of more than 770 molecular descriptors to establish a relationship between the lowest energy conformations and the IC50 values. The five best descriptors were selected to create and validate the model, which exhibited parameters that attested to its robustness and predictability. In summary, we observed that compounds with a para substitution and heavier groups (i.e. CF3 and NO2 substituents) had an enhanced HKT-inhibition profile. These compounds comprise a series described as AeHKT inhibitors via enzymatic inhibition experiments, opening the way to further the development of new substances with higher potency against HKT from Aedes aegypti.

Antimicrobial peptide induced colloidal transformations in bacteria-mimetic vesicles: Combining in silico tools and experimental methods.

With the growing challenges of bacteria becoming resistant to conventional antibiotics, antimicrobial peptides (AMPs) may offer a potential alternative. One of the most studied AMPs, the human cathelicidin derived AMP LL-37 is notable for its antimicrobial activity even though its mechanism of action is not fully understood yet. This work investigates the interaction of LL-37 with 1-Palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (POPG) vesicles, which were employed as a bacterial membrane model given the common presence of this phospholipid in the bacterial membrane. Experimental techniques including small angle X-ray scattering, transmission electron microscopy and dynamic light scattering were used to characterize the interactions among LL-37 and POPG. Molecular dynamics simulations complement the experimental studies with molecular-level insights into the process. LL-37 was discovered to actively and critically interact with the POPG vesicles, modifying the membrane curvature that eventually leads to structural transformations from vesicles to mixed micelles. The results shed light on the mechanisms underlying the interactions among LL-37 and bacteria mimetic vesicles and can guide the further development of AMP based antimicrobial materials and therapies.