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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.

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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.

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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.

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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.

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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/.

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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.

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Molecular dynamics (MD) simulations represent an essential tool in the toolbox of modern chemistry, enabling the prediction of experimental observables for a variety of chemical systems and processes and majorly impacting the study of biological membranes. However, the chemical diversity of complex lipids beyond phospholipids brings new challenges to well-established protocols used in MD simulations of soft matter and requires continuous assessment to ensure simulation reproducibility and minimize unphysical behavior. Lipopolysaccharides (LPS) are highly charged glycolipids whose aggregation in a lamellar arrangement requires the binding of numerous cations to oppositely charged groups deep inside the membrane. The delicate balance between the fully hydrated carbohydrate region and the smaller hydrophobic core makes LPS membranes very sensitive to the choice of equilibration protocol. In this work, we show that the protocol successfully used to equilibrate phospholipid bilayers when applied to complex lipopolysaccharide membranes occasionally leads to a small expansion of the simulation box very early in the equilibration phase. Although the use of a barostat algorithm controls the system dimension and particle distances according to the target pressure, fluctuation in the fleeting pressure occasionally enables a few water molecules to trickle into the hydrophobic region of the membrane, with spurious solvent buildup. We show that this effect stems from the initial steps of NPT equilibration, where initial pressure can be fairly high. This can be solved with the use of a stepwise-thermalization NVT/NPT protocol, as demonstrated for atomistic MD simulations of LPS/DPPE and lipid-A membranes in the presence of different salts using an extension of the GROMOS forcefield within the GROMACS software. This equilibration protocol should be standard procedure for the generation of consistent structural ensembles of charged glycolipids starting from atomic coordinates not previously pre-equilibrated. Although different ways to deal with this issue can be envisioned, we investigated one alternative that could be readily available in major MD engines with general users in mind.

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The enzyme 3-hydroxykynurenine transaminase (HKT) acts as an important enzyme in tryptophan catabolism of disease-carrier insects, e.g. Aedes aegypti and Anopheles gambiae. HKT is a detoxification enzyme that converts 3-hydroxykynurenine (a precursor for reactive nitrogen and oxygen species) into xanthurenic acid (stable and nontoxic compound). We have previously synthesized eleven new oxadiazole derivatives and demonstrated their noncompetitive inhibitory activity towards HKT from A. aegypti (https://doi.org/10.1016/j.bmc.2019.115252). These findings are presented in a research paper accompanying the present technical report on a new assay to overcome the fact that the substrate and product of the HKT-catalyzed reaction exhibit maximum absorption at very near wavelength (370 and 369 nm, respectively). The methods previously described in the literature rely on chromatographic separation prior to absorbance quantification, which limits their use for inhibitor screening. Due to HKT attractive features as a molecular target for larvicidal compounds, we report herein a new, faster and affordable methodology to evaluate the enzymatic activity of recombinant HKT, and therefore allow for the fast screening of potential HKT inhibitors via absorbance spectrophotometer. The advantages of the proposed methodology to previously described ones are:•It is faster and cheaper than HPLC-based assays because it does not require the use of chromatography columns and solvents to separate reaction components;•It uses of 96-well plates, enabling the simultaneous quantification of samples;•It can be applied to all transaminases that have xanthurenic acid as a product.

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Curvature is an intrinsic feature of biological membranes underlying vital cellular processes such as endocytosis, membrane fusion-fission, trafficking, and remodeling. The continuous expansion of the spatiotemporal scales accessible to computational simulations nowadays makes possible quasi-atomistic molecular dynamics simulations of these processes. In despite of that, computation of the shapes and curvatures associated with the dynamics of biological membranes remains challenging. For this reason, the effect of curvature is often neglected in the analysis of quantities essential for the accurate description of membrane properties (e.g., area and volume per lipid, density profiles, membrane thickness). We propose an algorithm for surface assessment via grid evaluation (SuAVE) that relies on the application of a radial base function to interpolate points scattered across an interface of any shape. This enables the representation of the chemical interface as fully differentiable so that related geometrical properties can be calculated through the straightforward employment of well-established differential geometry techniques. Hence, the effect of different types or degrees of curvature can be accurately taken into account in the calculations of structural properties of any interfaces regardless of chemical composition, asymmetry, and level of atom coarseness. The main functionalities implemented in SuAVE are featured for a number of tetraacylated and hexaacylated Lipid-A membranes of distinct curvatures and a surfactant micelle. We show that the properties calculated for moderately to highly curved membranes differ significantly between curvature-dependent and -independent algorithms. The SuAVE software is freely available from www.biomatsite.net/suave-software .

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The mosquito Aedes aegypti is the vector of arboviruses such as Zika, Chikungunya, dengue and yellow fever. These infectious diseases have a major impact on public health. The unavailability of effective vaccines or drugs to prevent or treat most of these diseases makes vector control the main form of prevention. One strategy to promote mosquito population control is the use of synthetic insecticides to inhibit key enzymes in the metabolic pathway of these insects, particularly during larval stages. One of the main targets of the kynurenine detoxification pathway in mosquitoes is the enzyme 3-hydroxykynurenine transaminase (HKT), which catalyzes the conversion of 3-hydroxykynurenine (3-HK) into xanthurenic acid (XA). In this work, we report eleven newly synthesized oxadiazole derivatives and demonstrate that these compounds are potent noncompetitive inhibitors of HKT from Ae. aegypti. The present data provide direct evidence that HKT can be explored as a molecular target for the discovery of novel larvicides against Ae. aegypti. More importantly, it ensures that structural information derived from the HKT 3D-structure can be used to guide the development of more potent inhibitors.

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An adsorbent-heater-thermometer nanomaterial, (ZIF-8,EuxTby)@AuNP, based on ZIF-8 (adsorbent), containing Eu3+ and/or Tb3+ ions (thermometer) and gold nanoparticles (AuNPs, heater) was designed, synthetized, characterized, and applied to controlled drug release. These composite materials were characterized as core-shell nanocrystals with the AuNPs being the core, around which the crystalline ZIF-8 has grown (shell) and onto which the lanthanide ions have been incorporated or chemosorbed. This shell of ZIF-8 acts as adsorbent of the drugs, the AuNPs act as heaters, while the luminescence intensities of the ligand and the lanthanide ions are used for temperature monitoring. This thermo-responsive material can be activated by visible irradiation to release small molecules in a controlled manner as established for the model pharmaceutical compounds 5-fluorouracil and caffeine. Computer simulations and transition state theory calculations shown that the diffusion of small molecules between neighboring pores in ZIF-8 is severely restricted and involves high-energy barriers. These findings imply that these molecules are uploaded onto and released from the ZIF-8 surface instead of being inside the cavities. This is the first report of ZIF-8 nanocrystals (adsorbents) containing simultaneously lanthanide ions as sensitive nanothermometers and AuNPs as heaters for controlled drug release in a physiological temperature range. These results provide a proof-of-concept that can be applied to other classes of materials, and offer a novel perspective on the design of self-assembly multifunctional thermo-responsive adsorbing materials that are easily prepared and promptly controllable.

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The complex solution behavior of polymer brushes is key to control their properties, including for biomedical applications and catalysis. The swelling behavior of poly(dimethyl aminoethyl methacrylate) (PDMAEMA) and poly(2-(methacryloyloxy)ethyl trimethylammonium chloride) (PMETAC) in response to changes in pH, solvent, and salt types has been investigated using atomistic molecular dynamics simulations. PDMAEMA and PMETAC have been selected as canonical models for weak and strong polyelectrolytes whose complex conformational behavior is particularly challenging for the development and validation of atomistic models. The GROMOS-derived atomic parameters reproduce the experimental swelling coefficients obtained from ellipsometry measurements for brushes of 5-15 nm thickness. The present atomistic models capture the protonated morphology of PDMAEMA, the swollen and collapsed conformations of PDMAEMA and PMETAC in good and bad solvents, and the salt-selective response of PMETAC. The modular nature of the molecular models allows for the simple extension of atomic parameters to a variety of polymers or copolymers.

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The ability of erythrocytes, infected by Plasmodium falciparum, to adhere to endothelial cells (cytoadherence) and to capture uninfected erythrocyte (rosetting) is the leading cause of death by severe malaria. Evidences link the binding of the adhesin Duffy Binding Like1-α (DBL1α) domain to the ABH histo-blood antigens with formation of rosettes. Inspired by this very close relationship between the disease susceptibility and individual blood type, here we investigate the structural requirements involved in the interaction of DBL1α with A, B and H histo-blood determinants and their subtypes. Our results evidence the high preference of DBL1α to A epitopes, in comparison to B and H epitopes. DBL1α interacts with ABH epitopes in subtype specific manner, presenting a remarkable affinity for type 2 structures, Fucα1-2Galß1-4GlcNAcß1, particularly the A2 epitope. The contacts made by DBL1α binding pocket and the ABH histo-blood groups were mapped by theoretical methods and supported by NMR experiments.

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Lipid-A is the causative agent of Gram-negative sepsis and is responsible for an increasingly high mortality rate among hospitalized patients. Compounds that bind Lipid-A can limit this inflammatory process. The cationic antimicrobial peptide polymyxin B (Pmx-B) is one of the simplest molecules capable of selectively binding to Lipid-A and may serve as a model for further development of Lipid-A binding agents. Gram-negative bacteria resistance to Pmx-B relies on the upregulation of a number of regulatory systems, which promote chemical modifications of the lipopolysaccharide (LPS) structure and leads to major changes in the physical-chemical properties of the outer membrane. A detailed understanding of how the chemical structure of the LPS modulates macroscopic properties of the outer membrane is paramount for the design and optimization of novel drugs targeting clinically relevant strains. We have performed a systematic investigation of Pmx-B binding to outer membrane models composed of distinct LPS chemotypes experimentally shown to be either resistant or susceptible to the peptide. Molecular dynamics simulations were carried out for Pmx-B bound to the penta- and hexa-acylated forms of Lipid-A (more susceptible) and Lipid-A modified with 4-amino-4-deoxy-l-arabinose (resistant) as well as the penta-acylated form of LPS Re (less susceptible). The present simulations show that upon binding to the bacterial outer membrane surface, Pmx-B promotes cation displacement and structural changes in membrane curvature and integrity as a function of the LPS chemotype susceptibility or resistance to the antimicrobial peptide.

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Cellular membranes are fundamental constituents of living organisms. Apart from defining the boundaries of the cells, they are involved in a wide range of biological functions, associated with both their structural and the dynamical properties. Biomembranes can undergo large-scale transformations when subject to specific environmental changes, including gel-liquid phase transitions, change of aggregation structure, formation of microtubules, or rupture into vesicles. All of these processes are dependent on a delicate interplay between intermolecular forces, molecular crowding, and entropy, and their understanding requires approaches that are able to capture and rationalize the details of all of the involved interactions. Molecular dynamics-based computational models at atom-level resolution are, in principle, the best way to perform such investigations. Unfortunately, the relevant spatial and time dimensionalities involved in membrane remodeling phenomena would require computational costs that are today unaffordable on a routinely basis. Such hurdles can be removed by coarse-graining the representations of the individual molecular components of the systems. This procedure anyway reduces the possibility of describing the chemical variations in the lipid mixtures composing biological membranes. New hybrid particle field multiscale approaches offer today a promising alternative to the more traditional particle-based simulations methods. By combining chemically distinguishable molecular representations with mesoscale-based computationally affordable potentials, they appear as one of the most promising ways to keep an accurate description of the chemical complexity of biological membranes and, at the same time, cover the required scales to describe remodeling events.

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Four chemotypes of the rough lipopolysaccharides (LPS) membrane from Pseudomonas aeruginosa were investigated by a combined approach of explicit water molecular dynamics (MD) simulations and Poisson-Boltzmann continuum electrostatics with the goal to deliver the distribution of the electrostatic potential across the membrane. For the purpose of this investigation, a new tool for modeling the electrostatic potential profile along the axis normal to the membrane, MEMbrane POTential (MEMPOT), was developed and implemented in DelPhi. Applying MEMPOT on the snapshots obtained by MD simulations, two observations were made: (a) the average electrostatic potential has a complex profile but is mostly positive inside the membrane due to the presence of Ca(2+) ions, which overcompensate for the negative potential created by lipid phosphate groups; and (b) correct modeling of the electrostatic potential profile across the membrane requires taking into account the water phase, while neglecting it (vacuum calculations) results in dramatic changes including a reversal of the sign of the potential inside the membrane. Furthermore, using DelPhi to assign different dielectric constants for different regions of the LPS membranes, it was investigated whether a single frame structure before MD simulations with appropriate dielectric constants for the lipid tails, inner, and the external leaflet regions, can deliver the same average electrostatic potential distribution as obtained from the MD-generated ensemble of structures. Indeed, this can be attained by using smaller dielectric constant for the tail and inner leaflet regions (mostly hydrophobic) than for the external leaflet region (hydrophilic) and the optimal dielectric constant values are chemotype-specific.

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The supra-molecular structure of LPS aggregates governs outer membrane permeability and activation of the host immune response during Gram-negative bacterial infections. Molecular dynamics simulations unveil at atomic resolution the subtle balance between cation hydration and cross-linking ability in modulating phase transitions of LPS membranes.

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Lipopolysaccharides (LPS) are the primary constituent of the outer membrane of Gram-negative bacteria such as Pseudomonas aeruginosa. Gram-negative bacteria can synthesize modified forms of LPS in response to environmental stimuli or due to genetic mutations, a process known as outer membrane remodeling. Chemical modifications of the LPS modulate the integrity and antibiotic susceptibility of bacterial outer membranes. It also governs microbial adhesion to tissues and artificial material surfaces. We have extended a previous model of the rough LPS to include four novel chemotypes rmlC, galU, LPS Re, and Lipid-A. Atomistic molecular dynamics (MD) simulations were performed for outer membrane models constituted of each LPS chemotypes and 1,2-dipalmitoyl-3-phosphatidylethanolamine. It is shown that the decrease in the LPS polysaccharide chain length leads to a significant increase in the diffusion coefficients for the Ca(2+) counterions, increase in acyl chain packing (decrease in membrane fluidity), and attenuation of the negative potential across the LPS surface as positive counterions becomes more exposed to the solvent. The electrostatic potential on the LPS surfaces reflects heterogeneous charge distributions with increasingly larger patches of positive and negative potentials as the polysaccharide chain length decreases. Such a pattern originates from the spatial arrangement of charged phosphate-Ca(2+) clusters in the LPS inner-core that becomes exposed in the membrane surface as monosaccharide units are lost in the shortest chemotypes LPS Re and Lipid-A. These MD-derived conformational ensembles reproduce experimental trends and provide atom-level structural information on the rough LPS chemotypes that can help to rationalize antibiotic resistance and bacterial adhesion processes.

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The mosquito Aedes aegypti is the vector agent responsible for the transmission of yellow fever and dengue fever viruses to over 80 million people in tropical and subtropical regions of the world. Exhaustive efforts have lead to a vaccine candidate with only 30% effectiveness against the dengue virus and failure to protect patients against the serotype 2. Hence, vector control remains the most viable route to dengue fever control programs. We have synthesized a class of 1,2,4-oxadiazole derivatives whose most biologically active compounds exhibit potent activity against Aedes aegypti larvae (ca. of 15 ppm) and low toxicity in mammals. Exposure to these larvicides results in larvae pigmentation in a manner correlated with the LC50 measurements. Structural comparisons of the 1,2,4-oxadiazole nucleus against known inhibitors of insect enzymes allowed the identification of 3-hydroxykynurenine transaminase as a potential target for these synthetic larvicides. Molecular docking calculations indicate that 1,2,4-oxadiazole compounds can bind to 3-hydroxykynurenine transaminase with similar conformation and binding energies as its crystallographic inhibitor 4-(2-aminophenyl)-4-oxobutanoic acid.

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