Molecular Modeling Methods Research Articles

Probing Fast Enantio-Recognition of Drugs with Multiple Chiral Centers by Electrospray-Tandem Mass Spectrometry and Its Mechanism

Chiral drugs are very complex substances since individual enantiomers may differ in pharmacological and toxic effects, making it necessary to analyze enantiomers separately. In this study, we investigated the chiral differentiation of two ezetimibe enantiomers (i.e., SRS-EZM and RSR-EZM) and their mechanisms in complex with β-cyclodextrins (CDs) and metal ions as the auxiliary ligands. For this purpose, two complementary approaches have been employed: electrospray-tandem mass spectrometry (ESI-MS/MS) with collision induced dissociation (CID) and molecular modeling methods, including density functional theory (DFT) calculations and molecular dynamics (MD) simulations. The results showed a good agreement between experimental and theoretical data. It was demonstrated that SRS-EZM can be easily distinguished from RSR-EZM by applying CID in ESI-MS/MS. SRS-EZM is likely to form a more stable complex with β-CD and metal ions, and thus the [SRS-EZM]-Cu-[β-CD] cluster is more energetically difficult to separate from the SRS-EZM molecule compared with RSR-EZM. Such a difference may be attributed to the interactions between the drug molecule and the metal ion, as well as the cavity shape changes of the β-CDs upon complexation with molecular guests. Therefore, enantiomers in chiral drug can be recognized as ternary complexes of metal-analyte-β-CD by ESI-MS/MS with CID.

Use of Schinus molle (Anacardiaceae) as a means of biological control against Trialeurodes vaporariorum (Aleyrodidae)

Greenhouse whiteflies, Trialeurodes vaporariorum, are very small sucker-whipper-type pests of the family Aleyrodidae. They cause considerable damage to greenhouse crops in the first order and show resistance to chemical insecticides. In this context, we dedicated this study to the control of this pest through the active ingredients extracted from the leaf and fruit part of the pepper tree, Schinus molle by inhibiting the chemosensory protein responsible mainly for capturing external stimuli in these polyphagous insects. By applying molecular modeling methods, including molecular docking, using software Molegro Virtual Docker version 2012.5.5.0, we tested the bioinsecticide potency of seven inhibitors. The results obtained show that the molecule beta- elemol is the best chemosensory protein inhibitor with a score of –82.6648 Kcal/mol and that it forms strong bonds with the active site amino acids of the protein.

Simulation of deformation on 3D organ models using haptic device

Günümüzde, bilgisayar grafiklerindeki gelişmeler sayesinde, birçok nesnenin asıllarına uygun şekilde sanal ortamda 3B modellenebilmesinde kayda değer gelişmeler elde edilmektedir. Tıp eğitiminde geliştirilen simülatörler ile organlar üzerinde doktor adaylarının çeşitli senaryolar kullanarak sayısız tekrar yapmalarına olanak sağlanarak pratik kazanmaları gerçekleştirilmektedir. Bu çalışmada, insan vücudu içerisinde bulunan safra, böbrek ve dalak gibi yumuşak dokuya sahip organların deformasyon algoritmaları ile yüzeysel benzetimlerinin yapılabilmesi için bir simülatör yazılım platformu geliştirilmiştir. Geliştirilen simülatör üzerinde, tasarlanan dokunsal cihaz donanımı ile anatomik yapılarına uygun şekilde 3B olarak modellenen organlar üzerine dokunulduğunda ya da çekme kuvveti uyguladığında model üzerinde gerçekleşen deformasyonun gerçekleşmesi sayesinde geri bildirim sağlanmıştır. Çalışmada, deformasyonun alınabilmesi için kütle yay ve moleküler modelleme metotları kullanılmıştır. Ek olarak, dokunsal cihaz ile modellenmiş örgü yapısı içerisinde hangi noktaya temas edildiğinin tespiti için çarpışma tespiti yöntemi tercih edilmiştir. Çalışma kapsamında geliştirilen simülatör üzerindeki tüm benzetimler, OpenGL kütüphanesi içerisinde bulunan fonksiyonlar kullanılarak gerçek zamanlı olarak gerçekleştirilmiştir. Ayrıca simülatörden toplamda 11 acemi ve uzman kullanıcı için simülasyon geri bildirimleri toplanmış ve her bir yumuşak doku için kullanıcıların elde ettikleri operasyon süreleri karşılaştırılmıştır. Yürütülen deneysel çalışmalar ve istatiksel analizler neticesinde, geliştirilen yazılım platformunun temas tespiti, tepki kuvveti, gerçek zamanlı benzetim ve deformasyon sonuçlarının görsel olarak ve hız açısından istenilen seviyede olduğu görülmüştür.

The evolutionary advantage of an aromatic clamp in plant family 3 glycoside exo-hydrolases

In the barley β-d-glucan glucohydrolase, a glycoside hydrolase family 3 (GH3) enzyme, the Trp286/Trp434 clamp ensures β-d-glucosides binding, which is fundamental for substrate hydrolysis during plant growth and development. We employ mutagenesis, high-resolution X-ray crystallography, and multi-scale molecular modelling methods to examine the binding and conformational behaviour of isomeric β-d-glucosides during substrate-product assisted processive catalysis that operates in GH3 hydrolases. Enzyme kinetics reveals that the W434H mutant retains broad specificity, while W434A behaves as a strict (1,3)-β-d-glucosidase. Investigations of reactant movements on the nanoscale reveal that processivity is sensitive to mutation-specific alterations of the tryptophan clamp. While wild-type and W434H utilise a lateral cavity for glucose displacement and sliding of (1,3)-linked hydrolytic products through the catalytic site without dissociation, consistent with their high hydrolytic rates, W434A does not adopt processive catalysis. Phylogenomic analyses of GH3 hydrolases disclose the evolutionary advantage of the tryptophan clamp that confers broad specificity, high catalytic efficiency, and processivity.

Structural Significance of His73 in F-Actin Dynamics: Insights from Ab Initio Study.

F-actin dynamics (polymerization and depolymerization) are associated with nucleotide exchange, providing the driving forces for dynamic cellular activities. As an important residue in the nucleotide state-sensing region in actin, His73 is often found to be methylated in natural actin and directly participates in F-actin dynamics by regulating nucleotide exchange. The interaction between His73 and its neighboring residue, Gly158, has significance for F-actin dynamics. However, this weak chemical interaction is difficult to characterize using classic molecular modeling methods. In this study, ab initio modeling was employed to explore the binding energy between His73 and Gly158. The results confirm that the methyl group on the His73 side chain contributes to the structural stability of atomistic networks in the nucleotide state-sensing region of actin monomers and confines the material exchange (Pi release) pathway within F-actin dynamics. Further binding energy analyses of actin structures under different nucleotide states showed that the potential model of His73/Gly158 hydrogen bond breaking in the material exchange mechanism is not obligatory within F-actin dynamics.

Water-soluble nickel (II) Schiff base complexes: Synthesis, structural characterization, DNA binding affinity, DNA cleavage, cytotoxicity, and computational studies

Two water-soluble nickel (II) Schiff base complexes were prepared and their interaction with fish sperm DNA (FS-DNA) was investigated by various methods including UV–vis spectroscopy, fluorescence spectroscopy, cyclic voltammetry, and viscometric measurements. Complex 1: [N,N′-bis{5-[(triphenyl phosphonium chloride)-methyl] salicylidine}-3,4-diaminobenzophenone]nickel(II) perchloride dihydrate: [Ni(5-CH2PPh3-3,4-salophen)] (ClO4)2.2 H2O was synthesized as a new complex and characterized by elemental analysis, IR, 1H NMR, thermal gravimetric analysis (TGA) and UV–vis spectroscopy. Complex 2: sodium [(N,N′-bis(5-sulfosalicyliden)-3, 4-diaminobenzophenone)aqua] nickel(II) hydrate: Na2[Ni (5-SO3-3,4-salbenz)(H2O)]. H2O was already synthesized by our research team, but in this study, its function as a DNA-binding compound was tested, and compared with the results of complex 1-DNA binding. The calculation of different constants using absorption and emission data, all confirmed the stronger binding ability of complex 1 than complex 2 with DNA. Different thermodynamic parameters showed the interactions between DNA and complexes were the type of hydrophobic interaction for complex 1 and electrostatic interaction for complex 2. Also, the negative values of free energy changes proved a spontaneous DNA binding process. Based on cell toxicity assay against two different cell lines including Jurkat and MCF-7, the effect of complex 1 was comparable to cisplatin, and the toxicity mechanism was further justified by bright field microscopy, flow cytometry, and cleavage of DNA in the presence of H2O2. Besides, the docking calculations suggested intercalation after measuring the lowest-energy between the complexes and DNA. For both complexes, all analytical, spectroscopic, and molecular modeling methods supported partial intercalation as the main binding mode between the complexes and DNA.

Kinetics and computational study of butyrylcholinesterase inhibition by methylrosmarinate: relevance to Alzheimer’s disease treatment

Butyrylcholinesterase (BChE) performs a significant function in Alzheimer’s disease progression. Experimental studies have shown that the function of BChE in the attenuation of cholinergic neurotransmission is essentially altered in brains of advanced AD patients. Here, using the complimentary methods of enzyme kinetic studies, molecular modeling and protein-ligand interaction profiling, we sought to reveal the mechanistic and structural features of BChE-methyrosmarinate interactions. Molecular docking simulations revealed that methylrosmarinate dwelled well in the active centre of BChE, where it got involved in stabilizing non-covalent associations with myriad subsites. Enzyme kinetic experiments showed that the Vm and Ks values were 156.20 ± 3.11 U mg−1 protein and 0.13 ± 0.01 μM, respectively. The inhibition studies showed that methylrosmarinate apparently inhibited BChE in a linear mixed manner, with an IC50 value of 10.31 μM and a Ki value of 3.73 ± 1.52 μM. Taken together, the extremely reduced Ki value and the increased number of BChE–methylrosmarinate interactions presuppose that methylrosmarinate is a good inhibitor of BChE, despite the fact that the mechanism for the effect of BChE inhibition on several pathological conditions in vivo remains unexplored.

Molecular Mimicry of the Rheumatoid Arthritis-Related Immunodominant T-Cell Epitope within Type II Collagen (CII260-270) by the Bacterial L-Asparaginase

The etiology of most autoimmune diseases, including rheumatoid arthritis (RA), remains unclear. Both genetic and environmental factors are believed to be involved in pathogenesis. Molecular mimicry is considered one of the mechanisms for the occurrence of autoimmune diseases. The aim of the study was to determine whether the bacterial peptide L-ASNase67-81, which mimics the immunodominant T-cell epitope CII259-273, can induce T-cell reactivity in blood samples from RA patients and healthy subjects through molecular mimicry. Using bioinformatic molecular modeling methods, we first determined whether the L-ASNase67-81 peptide binds to the HLA-DRB1*04:01 molecule and whether the formed MHCII–peptide complex interacts with the corresponding T-cell receptor. To validate the obtained results, leukocytes isolated from early RA patients and healthy individuals were stimulated in vitro with L-ASNase67-81 and CII259-273 peptides as well as with bacterial L-asparaginase or human type II collagen (huCII). The activated T cells (CD4+CD154+) were analyzed by flow cytometry (FACS), and the levels of cytokines produced (IL-2, IL-17A/F, and IFN-γ) were measured by ELISA. Our in silico analyses showed that the bacterial peptide L-ASNase67-81 binds better to HLA-DRB1*04:01 compared to the immunodominant T-cell epitope CII259-273, mimicking its structure and localization in the binding groove of MHCII. Six contact points were involved in the molecular interaction of the peptide with the TCR. FACS data showed that after in vitro stimulation with the L-ASNase67-81 peptide, the percentage of activated T cells (CD154+CD4+) was significantly increased in both cell cultures isolated from ERA patients and those isolated from healthy individuals, as higher values were observed for the ERA group (9.92 ± 0.23 vs. 4.82 ± 0.22). Furthermore, the ELISA assays revealed that after stimulation with L-ASNase67-81, a significant increase in the production of the cytokines IL-2, IL-17A/F, and IFN-γ was detected in the group of ERA patients. Our data showed that the bacterial L-ASNase67-81 peptide can mimic the immunodominant T-cell epitope CII259-273 and activate HLA-DRB1*04:01-restricted T cells as well as induce cytokine production in cells isolated from ERA patients. These results are the first to demonstrate that a specific bacterial antigen could play a role in the pathogenesis of RA, mimicking the immunodominant T-cell epitope from type II collagen.

Design, synthesis and biological evaluation of PD-1 derived peptides as inhibitors of PD-1/PD-L1 complex formation for cancer therapy

Over the past few years, many molecules such as monoclonal antibodies, affibodies, nanobodies, and small compounds have been designed and tested as inhibitors of PD-1/PD-L1 complex formation. Some of them have been successfully implemented into clinical oncology practice. However, the majority of these compounds have disadvantages and limitations, such as high production price, potential for immunogenicity and/or prolonged clearance. Thus, new inhibitors of the PD-1/PD-L1 immune checkpoints are needed. Recently, peptides emerged as potential novel approach for blocking receptor/ligand interaction. In the presented studies we have designed, synthesised and tested peptides, which are potential inhibitors of the PD-1/PD-L1 axis. The amino acid sequences of the designed peptides were based on the binding sites of PD-1 to PD-L1, as determined by the crystal structure of the protein complex and also based on MM/GBSA analysis. Interactions of the peptides with PD-L1 protein were confirmed using SPR, while their inhibitory properties were studied using cell-based PD-1/PD-L1 immune checkpoint blockade assays. The characterization of the peptides has shown that the peptides PD-1(119–142)T120C-E141C, PD-1(119–142)C123-S137C and PD-1(122–138)C123-S137C strongly bind to PD-L1 protein and disrupt the interaction of the proteins. PD-1(122–138)C123-S137C peptide was shown to have the best inhibitory potential from the panel of peptides. Its 3D NMR structure was determined and the binding site to PD-L1 was established using molecular modelling methods. Our results indicate that the PD-1 derived peptides are able to mimic the PD-1 protein and inhibit PD-1/PD-L1 complex formation.

The Candidate Molecules, RBD-ACE2 Binding Inhibitors to Prevent Sars-CoV-2 Infection

Angiotension-converting enzyme 2 (ACE2) is the host receptor of the serious-acute respiratory syndrome coronavirus 2 (Sars-CoV-2) spike protein. In this article, the interaction of ACE2 with the receptor binding domains (RBD) of Wuhan-Hu-1 and United Kingdom (UK) and South African (SA) variants is examined in silico. Their Gibbs free energies were computed using a protein binding energies prediction model. The interaction characteristics of RBDs with possible inhibitory compounds as well as a standard drug, Paxlovid, were also investigated, and Gibbs free energies were computed. Molecular modeling, molecular dynamics and molecular docking methods were employed and the results are compared and discussed.

Transport of Biologically Active Ultrashort Peptides Using POT and LAT Carriers.

Ultrashort peptides (USPs), consisting of 2–7 amino-acid residues, are a group of signaling molecules that regulate gene expression and protein synthesis under normal conditions in various diseases and ageing. USPs serve as a basis for the development of drugs with a targeted mechanism of action. The purpose of this review is to systematize the available data on USP transport involving POT and LAT transporters in various organs and tissues under normal, pathological and ageing conditions. The carriers of the POT family (PEPT1, PEPT2, PHT1, PHT2) transport predominantly di- and tripeptides into the cell. Methods of molecular modeling and physicochemistry have demonstrated the ability of LAT1 to transfer not only amino acids but also some di- and tripeptides into the cell and out of it. LAT1 and 2 are involved in the regulation of the antioxidant, endocrine, immune and nervous systems’ functions. Analysis of the above data allows us to conclude that, depending on their structure, di- and tripeptides can be transported into the cells of various tissues by POT and LAT transporters. This mechanism is likely to underlie the tissue specificity of peptides, their geroprotective action and effectiveness in the case of neuroimmunoendocrine system disorders.

Pharmacophore-based virtual screening, molecular docking and molecular dynamics simulations study for the identification of LIM kinase-1 inhibitors

LIM kinases (LIMKs) are a family of protein kinases involved in the regulation of actin dynamics. There are two isoforms of LIMKs i.e., LIMK1 and LIMK2. LIMK1 is expressed abundantly in neuronal tissues. LIMK1 plays an essential role in the degradation of dendritic spines, which are important for our higher brain functions, such as memory and learning. The inhibition of LIMK1 improves the size and density of dendritic spines and acts as a protective effect against Alzheimer's disease. In this study, we have adopted ligand-based drug design and molecular modelling methods to identify virtual hits. The pharmacophoric features of PF-00477736 were used to screen the Zinc15 compounds library. The identified hits were then passed through drug-likeliness and PAINS filters. Further, comprehensive docking and rigorous molecular dynamics simulation study afforded three virtual hits viz., ZINC504485634, ZINC16940431 and ZINC1091071. The hits showed a better docking score than the standard ligand, PF-00477736. The docking score was found to be –8.85, –7.50 and –7.68 kcal/mol. These hits exhibited optimal binding properties with the target in docking study, blood-brain barrier permeability, in silico pharmacokinetics and low predicted toxicity. Communicated by Ramaswamy H. Sarma

Computational Study of Thermodynamic Overpotentials of Quinone Reduction on Carbon Electrodes to Accelerate Organic Redox Flow Battery Research

Redox flow batteries (RFBs) offer advantages as compared to conventional batteries, such as the possibility of decoupling the energy density (volume and concentration of the electrolyte) and the power density (surface contact between electrode and electrolyte) of the battery. Organic redox flow batteries (ORFBs) have gained attention recently because they promise to be more eco-friendly and cheaper than their inorganic counterparts. Particularly, organic molecules are highly tunable in terms of both solubility and redox potential. Many families of organic molecules have been reported for this purpose, with quinones being particularly promising [Symons, 2021]. However, ORFBs are limited in terms of their cell potential and stability. To discover optimal molecules for ORFBs, many research groups have employed molecular modelling methods [Er et al., 2015]. These studies using density functional theory (DFT) in implicit solvents only compute the Nernst potential [Zhang et al., 2020] of the one-step coupled e- and H+ redox reaction (see Figure 1(a)), ignoring the overpotential of the reaction.Our study addresses two aspects going beyond this state of the art: 1) considering the intermediate, semiquinone, of the reaction (see Figure 1(b)) and thus the thermodynamic overpotential; and 2) incorporating the effects of the electrode/electrolyte interface, where the actual electrochemical processes take place (see Figure 1(c)). Since the exact atomic structure of the carbon felt is unknown, we use different model carbon morphologies to calculate the thermodynamic overpotential of the given reaction.Grand-canonical DFT in combination with the linearized Poisson–Boltzmann implicit solvent model [Abidi et al., 2020] was used to calculate the overpotential (versus SHE) of the two-step reduction reaction of non-substituted p-benzoquinone (BQ) on 6 different models for carbon surfaces - graphite basal plane (0001), and edges (1100), (1000), zigzag nanotube, armchair nanotube and Buckyball. The overpotential on these surfaces was found to be between 0.2-0.5 V. The solution-phase overpotential due to the intermediate was 0.3 V for non substituted quinone, and 0.5 V for both the substituted quinones that we studied (R=CN and R=OMe). At the graphite basal plane, while for the non-substituted quinone, the overpotential negligibly increased, for the substituted ones, the overpotential reduced by ~0.2 V each (see Figure 1(d)). This showed an interesting relationship between the substituents of the quinone and the electrode surface.Extending our study further, we explored the effect of defects in the graphite basal plane: substitutional B or N doping, and the Stone-Wales (SW) defect. We found that the overpotential of the BQ reduction reaction did not change for the SW defect, and it increased by 0.1 V if a C-atom was substituted by a B-atom and decreased by 0.1 V, for N-atom substitution. The N-doped surface had the least overpotential (0.25 V), which suggests that doping the electrode with nitrogen would make better electrodes. From these results, we concluded that the atomic-level morphology of the surface does not affect the overpotential of the reaction as much as the dopants in the surface do.In summary, our results demonstrate that grand-canonical DFT leads to detailed insights on the chemistry of ORFB at the electrode. From an electrochemical viewpoint, we show that estimating the overpotential of ORFB requires the consideration of the intermediate in the reduction reaction, and that substituting the quinones with CN or OMe decreases the overpotential on the electrode surface. Finally, the effect of the atomic-level morphology of the electrode does not significantly affect the overpotential, while substitutional N-doping lowers the overpotential.

Inhibitor loaded functional HNTs modified coatings towards corrosion protection in reinforced concrete environment

In this work, the corrosion inhibitor sodium D-gluconate (SD) was successfully loaded into halloysite nanotubes (HNTs). After that, SD-HNTs-A3@CS/SA smart nanocontainers, achieving controlled release properties of inhibitors, were prepared by the layer-by-layer (LbL) self-assembly method. The BET analysis found that the pore size inside the halloysite nanotubes increased after etching by 3 mol/L H2SO4. According to the TG results, the loading capacity of corrosion inhibitors increased to three times of the original HNTs. The pH-responsive properties of nanocontainers could be demonstrated by UV–Vis spectroscopy under acidic/basic conditions. Furthermore, SD-HNTs-A3@CS/SA nanoparticles were embedded in epoxy resin to fabricate a smart composite coating. When the SD-HNTs-A3@CS/SA content was 2 %, the composite coating exhibited superior anti-corrosion performance towards steel corrosion in concrete simulation solution (containing 3.5 wt% NaCl), with its impedance at 0.01 Hz maintaining 6.4 × 106 Ω·cm2 even after 18d of corrosion immersion. In addition, the anti-corrosion mechanism of SD for steel matrix was investigated by molecular modeling methods. These findings provide new insights into the preparation of smart coatings, expecting a wide range of applications in the corrosion protection of steel and other metals in reinforced concrete environments.

Inclusion complex of 20(S)-protopanaxatriol with modified β-cyclodextrin: Characterization, solubility, and interaction with bovine serum albumin

20(S)-protopanaxatriol (PPT) is one of the ginsenosides isolated from Panax ginseng which have many pharmaceutical activities. However, the poor water solubility of PPT restrict its applications. Herein, a novel bridged-bis-[6-(3,3’-(ethylenedioxy) bis (propylamine))-6-deoxy-β-cyclodextrin] (EDBA-bis-β-CD) was designed and synthesized, and the inclusion complex (IC) of EDBA-bis-β-CD with PPT was successfully prepared in the solid state, and characterized by UV, 1H NMR, 2D ROESY, FT-IR, XRD and SEM and molecular modelling methods. The continuous variation method analysis indicated that the stoichiometry of the IC was 1:1. UV–vis spectral analysis demonstrated the binding constant Ks was 995.94 M-1, and the solubility study showed that the solubility of PPT improved 290 times. The interaction of the IC with bovine serum albumin (BSA) was investigated via fluorescence spectroscopy. The results indicated that fluorescence quenching of BSA by IC was static quenching. Thermodynamic studies showed that van der Waals forces and hydrogen bonding play significant roles in interaction. The esterase-like activity of BSA in the presence of IC showed that it reduce the esterase activity of BSA in a competitive manner. Furthermore, molecular docking and molecular dynamics simulations for EDBA-bis-β-CD/PPT and BSA/IC systems were generated to provide information on the stability and the forces in the binding.

Structural characterization and computational investigations of three fluorine-containing ligands with a terphenyl core

Three linear terphenyl dicarboxylic acids with various number of fluorine addends have been prepared in a direct manner through Suzuki–Miyaura coupling. The central phenyl ring of the compounds is substituted with two or four fluorine atoms or two trifluoromethyl groups respectively. The structure and geometry of the dicarboxylic acids were confirmed by single crystal X-ray diffraction. The molecular structure of the three fluorine containing ligands was studied through molecular modeling methods. Hirshfeld surface analysis for each compound is presented.

Establishment and Molecular Modeling Study of Cyclodextrin-Based Synergistic Enantioseparation Systems with Three New Amino Acid Chiral Ionic Liquids as Additives in Capillary Electrophoresis.

Chiral ionic liquids (CILs) have attracted more and more attention due to their superior performance as chiral additives in capillary electrophoresis. In this work, based on the cyclodextrin (CD) derivatives and three new amino acid CILs (trifluoroacetate-L-Hydroxyproline, nitric acid-L-Hydroxyproline and trifluoroacetate-L-threonine), the new synergistic systems were established for chiral drug separation. In contrast to the traditional single glucosyl-β-CD (Glu-β-CD) separation system, the CIL/Glu-β-CD synergistic systems achieved improved resolution of three model drug racemates. Some experimental variables, such as CIL concentration, Glu-β-CD concentration, buffer pH, applied voltage, and the type and proportion of organic modifier, were optimized in the trifluoroacetate-L-Hydroxyproline/Glu-β-CD synergistic system. In addition, the recognition process in the synergistic system was studied through the molecular modeling method.

Molecular Modeling in Anion Exchange Membrane Research: A Brief Review of Recent Applications.

Anion Exchange Membrane (AEM) fuel cells have attracted growing interest, due to their encouraging advantages, including high power density and relatively low cost. AEM is a polymer matrix, which conducts hydroxide () ions, prevents physical contact of electrodes, and has positively charged head groups (mainly quaternary ammonium (QA) groups), covalently bound to the polymer backbone. The chemical instability of the quaternary ammonium (QA)-based head groups, at alkaline pH and elevated temperature, is a significant threshold in AEMFC technology. This review work aims to introduce recent studies on the chemical stability of various QA-based head groups and transportation of ions in AEMFC, via modeling and simulation techniques, at different scales. It starts by introducing the fundamental theories behind AEM-based fuel-cell technology. In the main body of this review, we present selected computational studies that deal with the effects of various parameters on AEMs, via a variety of multi-length and multi-time-scale modeling and simulation methods. Such methods include electronic structure calculations via the quantum Density Functional Theory (DFT), ab initio, classical all-atom Molecular Dynamics (MD) simulations, and coarse-grained MD simulations. The explored processing and structural parameters include temperature, hydration levels, several QA-based head groups, various types of QA-based head groups and backbones, etc. Nowadays, many methods and software packages for molecular and materials modeling are available. Applications of such methods may help to understand the transportation mechanisms of ions, the chemical stability of functional head groups, and many other relevant properties, leading to a performance-based molecular and structure design as well as, ultimately, improved AEM-based fuel cell performances. This contribution aims to introduce those molecular modeling methods and their recent applications to the AEM-based fuel cells research community.

Computational Characterization of N-acetylaspartylglutamate Synthetase: From the Protein Primary Sequence to Plausible Catalytic Mechanism

The methods of supercomputer molecular modeling are applied to characterize structure and dynamics of one of the key human brain enzymes, N-acetylaspartylglutamate synthetase. The three-dimensional all-atom models of the enzyme with the reactants in the active site are constructed in several steps, starting from pilot protein structure in the apo-form obtained with the AlphaFold2 from the protein primary sequence. Deposition of reactant molecules into the protein cavity, construction of the reaction intermediate and relaxation of the complex are carried out with the help of large-scale classical molecular dynamics calculations. On the top of the construct, molecular dynamics simulations with the quantum mechanics/molecular mechanics interaction potentials are performed for the most promising conformations of the model system. Analysis of the latter allows us to propose plausible catalytic mechanisms of chemical reactions in the enzyme active site. The applied computational strategy opens the way towards ab initio enzymology using modern supercomputer simulations.

Computational Modeling of the Interaction of Molecular Oxygen with the Flavin-dependent Enzyme RutA

Supercomputer molecular modeling methods are applied to characterize structure and dynamics of the flavin-dependent enzyme RutA in the complex with molecular oxygen. Following construction of a model protein system, molecular dynamics (MD) simulations were carried out using either classical force field interaction potentials or the quantum mechanics/molecular mechanics (QM/MM) potentials. Several oxygen-binding pockets in the protein cavities were located in these simulations. The QM/MM-based MD calculations rely on the interface between the quantum chemistry package TeraChem and the MD package NAMD. The results show a stable localization of the oxygen molecule in the enzyme active site. Static QM/MM calculations carried out with two different packages, NWChem and TURBOMOLE, allowed us to establish the structure of the RutA-O2 complex. Biochemical perspectives of the hallmark reaction of incorporating oxygen into organic compounds emerged from these simulations are formulated.