Molecular Dynamics Simulation Technique Research Articles

Tribological performance and lubrication mechanism of carbon nitride nanosheets as novel and high-efficiency additives for water lubrication

Recently, water-based nano-additives have attracted more attention with the resurrection of water lubrication owing to the increasing awareness of environmental protection and energy-saving. Highly water-dispersible carbon nitride nanosheets (C3N4 nanosheets), obtained via a high-yield and low-cost hydrothermal approach, were first used as a novel and environmentally-friendly nano-additive for water-based lubrication. The tribotest results exhibited that the tribological performances of C3N4 nanosheets in the water-based lubricant are highly sensitive to their adding concentrations. It was found that a C3N4 nanosheet concentration of 0.2 wt% could decrease the friction and wear in steel-steel contacts by 49.0% and 54.2%, respectively. The lubrication performances of C3N4 nanosheets as additives were much better than those of C3N4, attributed to their regular shape, good water dispersibility, and high reactivity. In addition, C3N4 nanosheets as additives exhibited a long service life even under harsh lubrication conditions. In addition, the molecular dynamics (MD) simulation technique was first employed to study the lubrication performances and lubrication regimes of C3N4 nanosheets. By combining the results of MD simulations and wear track surface analyses, the formation of water-based lubricating film and tribochemical film (mainly composed of organic compounds, metal nitrides, iron oxides, metal carbonates, and C3N4 nanosheets) coupled with the interlayer sliding and polishing effects of C3N4 nanosheets were primarily responsible for the excellent tribological performances of C3N4 nanosheets.

Comprehensive views toward the biomolecular recognition of an anticancer drug, leflunomide with human serum albumin

Biomolecular association of an anticancer drug, leflunomide (LEF) with human serum albumin (HSA), the leading ligands carrier in human circulation was characterized using biophysical (i.e., fluorescence, absorption and voltammetric) methods and computational (i.e., molecular docking and molecular dynamics simulation) techniques. Evaluations of fluorescence, absorption and voltammetric findings endorsed the complex formation between LEF and HSA. An inverse relationship of Stern-Volmer constant–temperature and hyperchromic shift of the protein’s absorption signal with addition of LEF confirmed the LEF quenched the HSA fluorescence through static process. Moderate nature of binding strength (binding constant = 2.76–4.77 × 104 M−1) was detected towards the LEF–HSA complexation, while the association process was naturally driven via hydrophobic interactions, van der Waals interactions and hydrogen bonds, as evident from changes in entropy (ΔS= + 19.91 J mol−1 K−1) and enthalpy (ΔH = − 20.09 kJ mol−1), and molecular docking assessments. Spectral analyses of synchronous and three-dimensional fluorescence validated microenvironmental fluctuations near Trp and Tyr residues upon LEF binding to the protein. LEF association with HSA significantly defended temperature-induced destabilization of the protein. Although LEF was found to attach to HSA at Sudlow’s sites I and II, but exhibited greater preference toward its site I, as detected by the investigations of competitive site-marker displacement. Molecular dynamics simulation assessment revealed that the complex attained equilibrium throughout simulations, showing the LEF–HSA complex constancy. Communicated by Ramaswamy H. Sarma

Investigation of molecular details of a bacterial cationic amino acid transporter (GkApcT) during arginine transportation using molecular dynamics simulation and umbrella sampling techniques.

Cationic amino acid transporters (CATs) facilitate arginine transport across membranes and maintain its levels in various tissues and organs, but their overexpression has been associated with severe cancers. A recent study identified the alternating access mechanism and critical residues involved in arginine transportation in a cationic amino acid transporter from Geobacillus kaustophilus (GkApcT). Here, we used molecular dynamics (MD) simulation methods to investigate the transportation mechanism of arginine (Arg) through GkApcT. The results revealed that arginine strongly interacts with specific binding site residues (Thr43, Asp111, Glu115, Lys191, Phe231, Ile234, and Asp237). Based on the umbrella sampling, the main driving force for arginine transport is the polar interactions of the arginine with channel-lining residues. An in-depth description of the dissociation mechanism and binding energy analysis brings valuable insight into the interactions between arginine and transporter residues, facilitating the design of effective CAT inhibitors in cancer cells. The membrane-protein system was constructed by uploading the prokaryotic CAT (PDB ID: 6F34) to the CHARMM-GUI web server. Molecular dynamics simulations were done using the GROMACS package, version 5.1.4, with the CHARMM36 force field and TIP3P water model. The MM-PBSA approach was performed for determining the arginine binding free energy. Furthermore, the hotspot residues were identified through per-residue decomposition analysis. The characteristics of the channel such as bottleneck radius and channel length were analyzed using the CaverWeb 1.1 web server. The proton wire inside the transporter was investigated based on the classic Grotthuss mechanism. We also investigated the atomistic details of arginine transportation using the path-based free energy umbrella sampling technique (US).

Probing the origins of programmed death ligand-1 inhibition by implementing machine learning-assisted sequential virtual screening techniques.

PD-L1 is a key immunotarget involved in binding to its receptor PD-1. PD-L1/PD-1 interface blocking using antibodies (or small molecules) is the central area of interest for tumor suppression in various cancers. Blocking the PD-L1/PD-1 pathway in the tumor cells results in its immune activation and destruction, and thereby restoring the T-cell proliferation and cytokine production. The active binding site interface residues of PD-L1/PD-1 were experimentally known and proven by structural biology and site-directed mutagenesis studies. Structure-based molecular design technique was employed to identify the inhibitors for blocking the PD-L1/PD-1 interface. Nine hits to leads were identified from the SPECS small molecule database by machine learning, molecular docking, and molecular dynamics simulation techniques. Following this, a machine learning-assisted QSAR modeling approach was implemented using ChEMBL database to gain insights into the inhibitory potential of PD-L1 inhibitors and predict the activity of our previously screened nine hit molecules. The best leads identified in the present study bind strongly with the active sites of PD-L1/PD-1 interface residues, which include A121, M115, I116, S117, I54, Y56, D122, and Y123. These computational leads are considered promising molecules for furtherin vitroandin vivoanalysis to be developed as potential PD-L1 checkpoint inhibitors to cure different types of cancers.

Carboxy styrene-butadiene latex and PVA fiber co-modified rubber concrete - experiment and molecular dynamics simulation

ABSTRACT Rubber concrete (RC) is a new environmentally friendly composite material, there are many weak interfaces and pores inside it, which degrade its mechanical properties. To address this problem, this study coordinates the modification of RC with carboxy styrene butadiene latex (CSBL) and polyvinyl alcohol (PVA) fibers to improve its mechanical properties. From mechanical properties experiments, it was found that 0.6% cement mass of PVA fiber and 10% cement mass of CSBL could increase the compressive and shear strengths by 12.4% and 30%, respectively. A series of microscopic tests (Scanning Electron Microscope-SEM, X-ray diffraction-XRD, Fourier Transform Infrared Spectrometer-FTIR) revealed that PVA fibers limited the development of cracks and CSBL caused further hydration of unhydrated cement to produce more cement gel, which in turn filled the internal pore structure of concrete. Molecular dynamics simulation techniques were used to create hydrated calcium silicate (C-S-H)/CSBL, rubber/CSBL and PVA/CSBL models. Dynamic and static simulations of the interfaces based on the above models revealed that CSBL is used to enhance the bonding between materials through a large number of stable hydrogen and ionic bonds. In this study, the enhanced RC is analyzed at multiple scales, which provides experimental and theoretical support for its application in engineering.

Computational study on the effect of aspect ratio on Young’s modulus of boron nitride nanosheets

The effect of the aspect ratio on Young’s modulus (E) of boron nitride nanosheets (BNNS) was evaluated using molecular dynamics simulation techniques employing the Tersoff potential field. The aspect ratio (L/B) of BNNS may influence the elastic properties; therefore, the values are varied from 2 to 12. Our results revealed that the E of BNNS decreased with an increase in the aspect ratio up to 9 and then became stable in both the armchair and zigzag directions. It is anticipated that the result will provide a beneficial understanding of the elastic properties of BNNS, which can aid in the design and implementation of structured and tailored NEMS devices, transistors, sensors, lightweight materials, and automotive sectors.

PVA fiber/cement-based interface in silane coupler KH560 reinforced high performance concrete – Experimental and molecular dynamics study

PVA fiber reinforced cementitious composites are becoming more and more popular. Due to the difference in physical and chemical properties of the materials, there is a problem of weak interfacial properties between PVA and cement.In order to solve this problem, this study adopts the means of pretreatment of PVA fibers with silane coupler KH560 (KH560), and the strengthening mechanism of KH560 is systematically investigated by means of multi-scale analysis. From the macroscopic test data, it was found that the flexural strength of PVA fiber concrete at 28 days was enhanced by 16% maximally when the PVA fiber content was 0.9%. A series of microscopic tests (Scanning Electron Microscope-SEM, X-ray Diffraction- XRD, Fourier Transform Infrared Spectrometer-FTIR) characterizing the interfacial properties of the KH560-modified material revealed the reason why the pretreated PVA could be better embedded in the cementitious base. Because the addition of KH560 not only generates more gel material and increases the tightness of the interfacial structure between the fiber and the cementitious base, but also reacts with the cement to produce Si-O-Si chemical bonds.A molecular model of PVA and a gel model of calcium silicate hydrate (C-S-H), the main product of cement, were constructed using the method of molecular dynamics (MD) simulation technique. The interaction between fibers and C-S-H was found to be not only mechanical occlusion, but also unstable hydrogen and ionic bonds between PVA molecules and C-S-H. The Si-O-Si bond is very important. In summary, the strengthening mechanism of KH560 and PVA synergistically on concrete is summarized by the analysis of different scales. It also provides theoretical and experimental support for the application of KH560 and PVA fibers in composite materials.

Stability of Nanopeptides: Structure and Molecular Exchange of Self-assembled Peptide Fibers.

Often nanostructures formed by self-assembly of small molecules based on hydrophobic interactions are rather unstable, causing morphological changes or even dissolution when exposed to changes in aqueous media. In contrast, peptides offer precise control of the nanostructure through a range of molecular interactions where physical stability can be engineered in and, to a certain extent, decoupled from size via rational design. Here, we investigate a family of peptides that form beta-sheet nanofibers and demonstrate a remarkable physical stability even after attachment of poly(ethylene glycol). We employed small-angle neutron/X-ray scattering, circular dichroism spectroscopy, and molecular dynamics simulation techniques to investigate the detailed nanostructure, stability, and molecular exchange. The results for the most stable sequence did not reveal any structural alterations or unimer exchange for temperatures up to 85 °C in the biologically relevant pH range. Only under severe mechanical perturbation (i.e., tip sonication) would the fibers break up, which is reflected in a very high activation barrier for unimer exchange of ∼320 kJ/mol extracted from simulations. The results give important insight into the relation between molecular structure and stability of peptide nanostructure that is important for, e.g., biomedical applications.

Deuterium occupation of interatomic hole sites in Ni67Zr33 amorphous alloy

The occupation of interatomic hole sites by deuterium in a deuterated Ni67Zr33 amorphous alloy was investigated using diffraction measurements and a combination of reverse Monte Carlo and molecular dynamics simulation techniques. The results show that deuterium atoms occupy various types of polyhedral hole sites, as well as tetrahedral ones. The occupation by a deuterium atom of a tetrahedral hole site causes volume expansion, but that of a larger polyhedral hole site does not cause a substantial change in the volume. Each deuterium atom is chemically bonded with 4–6 metal atoms, even for a larger polyhedral hole formed by seven or more metal atoms.

Network Pharmacology, Molecular Docking and Molecular Dynamics to Explore the Potential Immunomodulatory Mechanisms of Deer Antler.

The use of deer antlers dates back thousands of years in Chinese history. Deer antlers have antitumor, anti-inflammatory, and immunomodulatory properties and can be used in treating neurological diseases. However, only a few studies have reported the immunomodulatory mechanism of deer antler active compounds. Using network pharmacology, molecular docking, and molecular dynamics simulation techniques, we analyzed the underlying mechanism by which deer antlers regulate the immune response. We identified 4 substances and 130 core targets that may play immunomodulatory roles, and the beneficial and non-beneficial effects in the process of immune regulation were analyzed. The targets were enriched in pathways related to cancer, human cytomegalovirus infection, the PI3K-Akt signaling pathway, human T cell leukemia virus 1 infection, and lipids and atherosclerosis. Molecular docking showed that AKT1, MAPK3, and SRC have good binding activity with 17 beta estradiol and estrone. Additionally, the molecular dynamics simulation of the molecular docking result using GROMACS software (version: 2021.2) was performed and we found that the AKT1-estrone complex, 17 beta estradiol-AKT1 complex, estrone-MAPK3 complex, and 17 beta estradiol-MAPK3 complex had relatively good binding stability. Our research sheds light on the immunomodulatory mechanism of deer antlers and provides a theoretical foundation for further exploration of their active compounds.

Structure-based virtual screening, molecular docking, and molecular dynamics simulation approaches for identification of new potential inhibitors of class a β-lactamase enzymes

Bacteria are smart organisms that create drug resistance by decreasing the effect of antibiotics in different ways, such as secretion of the β-lactamase enzymes. Finding the compounds that can act as the inhibitors of these enzymes is a great help in reducing drug resistance and treat all types of infections. In this study, using molecular docking and molecular dynamics simulation techniques, we introduced two Relebactam substructures as new inhibitors of class A β-lactamase enzymes. Results of molecular docking show that the conformation of these two compounds in the active site of class A β-lactamase enzymes has a good match with Relebactam and their binding affinity to enzymes is equal to or better than Relebactam. Results showed a good tendency for binding and the formation of van der Waals and hydrogen interactions between the desired compounds and the β-lactamase enzymes. The results of the analysis of the molecular dynamics simulation trajectories showed that in the presence of the desired compounds, the second structures of the enzymes did not undergo many changes and in none of the systems, the binding of the compounds to the enzyme did not cause much instability, and in most cases made the structure stable. The hydrogen bonds were stable during the simulation time and in most cases, the new compounds formed more hydrogen bonds and had better binding affinity than Relebactam confirms the docking results. The results of this study can be helpful in designing new beta-lactamase inhibitors and new treatment methods to deal with drug resistance. Communicated by Ramaswamy H. Sarma

Use of computational and wet lab techniques to examine the molecular association between a potent hepatitis C virus inhibitor, PSI-6206 and human serum albumin.

This study explores the plausible molecular interaction between a potent hepatitis C virus inhibitor, PSI-6206 (PSI), and human serum albumin (HSA), a primary transporter in blood plasma. Results obtained from both computational viz. molecular docking and molecular dynamics (MD) simulation and wet lab techniques such as UV absorption, fluorescence, circular dichroism (CD), and atomic force microscopy (AFM) complemented each other. While docking results identified PSI binding to subdomain IIA (Site I) of HSA by forming six hydrogen bonds, MD simulations signified the complex stability throughout the 50,000ps. A consistent cutback in the Stern-Volmer quenching constant (Ksv) along with rising temperatures supported the static mode of fluorescence quenching in response to PSI addition and implied the development of the PSI-HSA complex. This discovery was backed by the alteration of the HSA UV absorption spectrum, a larger value (>1010 M-1.s-1) of the bimolecular quenching rate constant (kq) and the AFM-guided swelling of the HSA molecule, in the presence of PSI. Moreover, the fluorescence titration results revealed a modest binding affinity (4.27-6.25×103 M-1) in the PSI-HSA system, involving hydrogen bonds, van der Waals and hydrophobic interactions, as inferred from ΔS = + 22.77Jmol-1 K-1 and ΔH = - 11.02 KJ mol-1values. CD and 3D fluorescence spectra reminded significant adjustment in the 2° and 3° structures and modification in the Tyr/Trp microenvironment of the protein in the PSI-bound state. The results obtained from drug competing experiments also advocated the binding location of PSI in HSA as Site I.

Preparation and comprehensive characterization of C16MImCl/MT for adsorbing cationic dyes.

Dyeing wastewater in various industries poses a great threat to the environment. Montmorillonite (MT) is widely used in wastewater treatment because of its abundant reserves and strong exchange capacity. However, natural MT has low affinity for organic pollutants and needs to be organically modified. In order to improve the adsorption capacity of MT to cationic dyes [Congo red (CR)], using ionic liquid [1-hexadecyl-3-methylimidazolium chloride (C16MImCl)] as organic modifier, the optimal preparation process of C16MImCl/MT was determined by response surface methodology. The C16MImCl/MT was comprehensively characterized by utilizing the techniques of XRD, FTIR, TG, BET, SEM, and molecular dynamics simulation. All the research results showed that C16MImCl is successfully inserted into the layers of MT, and the basal interplanar spacing and average pore size of MT are obviously increased. The C16MImCl/MT is a mesoporous material, which shows strong adsorption capacity for CR, and its CR unit adsorption capacity (CRUAC) could reach 940.200mg/g, which is about three times that of magnetic graphene oxide and bentonite/expanded graphite.

Pharmacokinetics and drug-likeness of anti-cancer traditional Chinese medicine: molecular docking and molecular dynamics simulation study

MCM7 (Minichromosome Maintenance Complex Component 7) is a component of the DNA replication licensing factor, which controls DNA replication. The MCM7 protein is linked to tumor cell proliferation and has a function in the development of several human cancers. Several types of cancer may be treated by inhibiting the protein, as it is strongly produced throughout this process. Significantly, Traditional Chinese Medicine (TCM), which has a long history of clinical adjuvant use against cancer, is rapidly gaining traction as a valuable medical resource for the development of novel cancer therapies, including immunotherapy. Therefore, the goal of the research was to find small molecular therapeutic candidates against the MCM7 protein that may be used to treat human cancers. A computational-based virtual screening of 36,000 natural TCM libraries is carried out for this goal using a molecular docking and dynamic simulation technique. Thereby, ∼8 novel potent compounds i.e., ZINC85542762, ZINC95911541, ZINC85542617, ZINC85542646, ZINC85592446, ZINC85568676, ZINC85531303, and ZINC95914464 were successfully shortlisted, each having the capacity to penetrate the cell as potent inhibitors for MCM7 to curb this disorder. These selected compounds were found to have high binding affinities compared to the reference (AGS compound) i.e. < −11.0 kcal/mol. ADMET and pharmacological properties showed that none of these 8 compounds poses any toxic property (carcinogenicity) and have anti-metastatic, and anticancer activity. Additionally, MD simulations were run to assess the compounds’ stability and dynamic behavior with the MCM7 complex for about 100 ns. Finally, ZINC95914464, ZINC95911541, ZINC85568676, ZINC85592446, ZINC85531303, and ZINC85542646 are identified as highly stable within the complex throughout the 100 ns simulations. Moreover, the results of binding free energy suggested that the selected virtual hits significantly bind to the MCM7 which implied these compounds may act as a potential MCM7 inhibitor. However, in vitro testing protocols are required to further support these results. Further, assessment through various lab-based trial methods can assist with deciding the action of the compound that will give options in contrast to human cancer immunotherapy. Communicated by Ramaswamy H. Sarma

Study of the binding interaction of salmon sperm DNA with nintedanib, a tyrosine kinase inhibitor using multi-spectroscopic, thermodynamic, and in silico approaches

The study of the intermolecular binding interaction of small molecules with DNA can guide the rational drug design with greater efficacy and improved or more selective activity. In the current study, nintedanib’s binding interaction with salmon sperm DNA (ssDNA) was thoroughly investigated using UV-vis spectrophotometry, spectrofluorimetry, ionic strength measurements, viscosity measurements, thermodynamics, molecular docking, and molecular dynamic simulation techniques under physiologically simulated conditions (pH 7.4). The obtained experimental results showed that nintedanib and ssDNA had an apparent binding interaction. Nintedanib’s binding constant (Kb ) with ssDNA, as determined using the Benesi-Hildebrand plot, was 7.9 × 104 M−1 at 298 K, indicating a moderate binding affinity. The primary binding contact forces were hydrophobic and hydrogen bonding interactions, as verified by the enthalpy and entropy changes (ΔH0 and ΔS0 ), which were − 16.25 kJ.mol−1 and 39.30 J mol−1 K−1, respectively. According to the results of UV-vis spectrophotometry, viscosity assays, and competitive binding interactions with ethidium bromide or rhodamine B, the binding mode of nintedanib to ssDNA was minor groove. Molecular docking and molecular dynamic simulation studies showed that nintedanib fitted into the B-DNA minor groove’s AT-rich region with high stability. This study can contribute to further understanding of nintedanib’s molecular mechanisms and pharmacological effects.

Nucleobase Specific Understanding about the Interaction of Antimalarial Drug Chloroquine with Duplex DNA.

Antimalarial action of a drug is closely associated with the interaction with the parasite's DNA. Hence, in this study, the interaction of an important antimalarial drug, chloroquine (CLQ), has been investigated with six different sequences of DNA having pure adenine (A)-thymine (T) and pure cytosine (C)-guanine (G) as well as mixed nucleobases to achieve the nucleobase level of information in the binding of antimalarial drug with DNA along with binding induced stabilization/destabilization of DNA using different spectroscopic methods and molecular dynamics simulation technique. Further, the experiments have been also performed with 4-amino-7-chloroquinoline (7CLQ), an analogue of CLQ, to understand the role of the quinoline ring and side chain of CLQ in the binding with different sequences of DNA. The binding efficiency of CLQ with any sequence of DNA is higher than 7CLQ suggesting that the presence of charge on CLQ plays a prominent role in DNA binding. The data suggest that the binding of drug as well as induced stabilization of DNA depends significantly on the nature as well as the arrangement of the nucleobases. In general, the binding of CLQ with pure CG DNA is higher than with pure AT DNA; moreover, it prefers an alternate order of CG/AT than continual nucleobases in duplex DNA. CLQ predominately accommodates in the minor groove of AT DNA and prefers to form hydrogen bond mostly with the adenine nucleobase. In contrast to AT DNA, CLQ intrudes into the both major and minor grooves, but it is primarily accommodated into the major groove of CG DNA. CLQ forms a hydrogen bond mainly with guanine in the major groove and cytosine in the minor groove of CG DNA which enhances the binding of CLQ compared to AT DNA as well as induces higher stabilization in CG DNA. The molecular level information obtained about the functional group responsible for the interaction of CLQ as well as the role of chemical nature of nucleobases along with its ordering on the binding of CLQ with DNA may be useful in comprehensive understanding of its action mechanism.

Anticorrosion performance assessment of silane-modified chitosan/epoxy primer coatings on mild steel in saline environment using computational simulation techniques.

The anticorrosion performance of silane-modified chitosan/epoxy primer coatings was evaluated using quantum chemical computations (QCC) and molecular dynamics simulation (MDS) techniques. The objective was to appraise the molecular/atomistic level performance of silane-modified chitosan/epoxy primer coating system on mild steel in saline water to be able to design robust anticorrosion epoxy nanocomposite primer coating for marine application. The QCC showed that quantum parameters for (3-aminopropyl) trimethoxy silane-modified chitosan nanocluster (AMCN) are optimum and therefore correspond to high corrosion protective capability. The adsorption energies (Eads) for AMCN/epoxy, tetraethoxysilane-modified chitosan/epoxy, chitosan-modified epoxy, and unmodified epoxy coatings were found to be - 3094.65, - 2,630.00, - 2,305.77, and - 1,189.33kcal/mol, respectively. The high negative value of Eads indicates the coating molecules interacted and adsorbed strongly on the mild steel surface. Hence, AMCN/epoxy coating is potentially most corrosion-resistant than the others. Further, it is established that shorter bond length corresponds to higher bond strength and therefore indicates chemical interaction. Thus, the radial distribution function showed the bond lengths between atoms of the AMCN and mild steel surfaces were shorter than those of other molecules. Overall, AMCN/epoxy coating molecules possess good anticorrosion properties and therefore would perform well if deployed for service in saline environments.

Characterization of RNA polymerase II trigger loop mutations using molecular dynamics simulations and machine learning.

Catalysis and fidelity of multisubunit RNA polymerases rely on a highly conserved active site domain called the trigger loop (TL), which achieves roles in transcription through conformational changes and interaction with NTP substrates. The mutations of TL residues cause distinct effects on catalysis including hypo- and hyperactivity and altered fidelity. We applied molecular dynamics simulation (MD) and machine learning (ML) techniques to characterize TL mutations in the Saccharomyces cerevisiae RNA Polymerase II (Pol II) system. We did so to determine relationships between individual mutations and phenotypes and to associate phenotypes with MD simulated structural alterations. Using fitness values of mutants under various stress conditions, we modeled phenotypes along a spectrum of continual values. We found that ML could predict the phenotypes with 0.68 R2 correlation from amino acid sequences alone. It was more difficult to incorporate MD data to improve predictions from machine learning, presumably because MD data is too noisy and possibly incomplete to directly infer functional phenotypes. However, a variational auto-encoder model based on the MD data allowed the clustering of mutants with different phenotypes based on structural details. Overall, we found that a subset of loss-of-function (LOF) and lethal mutations tended to increase distances of TL residues to the NTP substrate, while another subset of LOF and lethal substitutions tended to confer an increase in distances between TL and bridge helix (BH). In contrast, some of the gain-of-function (GOF) mutants appear to cause disruption of hydrophobic contacts among TL and nearby helices.

Structural dynamics and functional analysis of Saprolegnia parasitica chitin synthases 5 in a phospholipid bilayer

Saprolegnia parasitica is an oomycete responsible for a fish disease called saprolegniosis, which poses an economic and environmental burden on aquaculture production. In Saprolegnia, CHS5 of S. parasitica (SpCHS5) contains an N-terminal domain, a catalytic domain of the glycosyltransferase −2 family containing a GT-A fold, and a C-terminal transmembrane domain. No three-dimensional structure of SpCHS5 is reported yet disclosing the structural details of this protein. We have developed a structural model of full-length SpCHS5 and validated it by molecular dynamics simulation technique. From the 1 microsecond simulations, we retrieved the stable RoseTTAFold model SpCHS5 protein to explain characteristics and structural features. Furthermore, from the analysis of the movement of chitin in the protein cavity, we assumed that ARG 482, GLN 527, PHE 529, PHE 530, LEU 540, SER 541, TYR 544, ASN 634, THR 641, TYR 645, THR 641, ASN 772 residues as a main cavity lining site. In SMD analysis, we investigated the opening of the transmembrane cavity required for chitin translocation. The pulling of chitin from the internal cavity to the extracellular region was observed through steered molecular dynamics simulations. A comparison of the initial and final structures of chitin complex showed that there’s a transmembrane cavity opening in the simulations. Overall, this present work will help us understand the structural and functional basis of CHS5 and design inhibitors against SpCHS5. Communicated by Ramaswamy H. Sarma

Pangenome profiling of novel drug target against vancomycin-resistant Enterococcus faecium

Enterococcus faecium is a frequent causative agent of nosocomial infection mainly acquired from outgoing hospital patients (Hospital Acquired Infection—HAIs). They are largely involved in the outbreaks of bacteremia, UTI, and endocarditis with a high transmissibility rate. The recent emergence of VRE strain (i.e. vancomycin resistant enterococcus) turned it into high priority pathogen for which new drug research is of dire need. Therefore, in current study, pangenome and resistome analyses were performed for available antibiotic-resistant genomes (n = 216) of E. faecium. It resulted in the prediction of around 5,059 genes as an accessory gene, 1,076 genes as core and 1,558 genes made up a unique genome fraction. Core genes common to all strains were further used for the identification of potent drug targets by applying subtractive genomics approach. Moreover, the COG functional analysis showed that these genomes are highly enriched in metabolic pathways such as in translational, ribosomal, proteins, carbohydrates and nucleotide transport metabolism. Through subtractive genomics it was observed that 431 proteins were non-homologous to the human proteome, 166 identified as essential for pathogen survival while 26 as potential and unique therapeutic targets. Finally, 3-dehydroquinate dehydrogenase was proposed as a potent drug target for further therapeutic candidate identification. Moreover, the molecular docking and dynamic simulation technique were applied to performed a virtual screening of natural product libraries (i.e., TCM and Ayurvedic compounds) along with 3-amino-4,5-dihydroxy-cyclohex-1-enecarboxylate (DHS) as a standard compound to validate the study. Consequently, Argeloside I, Apigenin-7-O-gentiobioside (from Ayurvedic library), ZINC85571062, and ZINC85570908 (TCM library) compounds were identified as potential inhibitors of 3-dehydroquinate dehydrogenase. The study proposed new compounds as novel therapeutics, however, further experimental validation is needed as a follow-up. Communicated by Ramaswamy H. Sarma