PFAS-Biomolecule Interactions: Case Study Using Asclepios Nodes and Automated Workflows in KNIME for Drug Discovery and Toxicology.

The Asclepios suite of KNIME nodes represents an innovative solution for conducting cheminformatics and computational chemistry tasks, specifically tailored for applications in drug discovery and computational toxicology. This suite has been developed using open-source and publicly accessible software. In this chapter, we introduce and explore the Asclepios suite through the lens of a case study. This case study revolves around investigating the interactions between per- and polyfluorinated alkyl substances (PFAS) and biomolecules, such as nuclear receptors. The objective is to characterize the potential toxicity of PFAS and gain insights into their chemical mode of action at the molecular level. The Asclepios KNIME nodes have been designed as versatile tools capable of addressing a wide range of computational toxicology challenges. Furthermore, they can be adapted and customized to accomodate the specific needs of individual users, spanning various domains such as nanoinformatics, biomedical research, and other related applications. This chapter provides an in-depth examination of the technical underpinnings and foundations of these tools. It is accompanied by a practical case study that demonstrates the utilization of Asclepios nodes in a computational toxicology investigation. This showcases the extendable functionalities that can be applied in diverse computational chemistry contexts. By the end of this chapter, we aim for readers to have a comprehensive understanding of the effectiveness of the Asclepios node functions. These functions hold significant potential for enhancing a wide spectrum of cheminformatics applications.

Role of urea in the retention of DON in soil by clay minerals: Analysis based upon molecular weight.

As a widely used fertilizer, urea significantly promotes the leaching of dissolved organic nitrogen (DON) in soils and aggravates nitrogen contamination in groundwater. Clay minerals are considered the most important factor in retaining DON. However, the effect of urea on the retention of DON with different molecular weights by clay minerals is unknown. In this study, the retention of both low-molecular weight DON (LMWD) and high-molecular weight DON (HMWD) by clay minerals in the presence of urea was investigated. For this purpose, batch adsorption and soil column leaching experiments, characterization analysis (Fourier transform infrared spectroscopy X-ray diffraction, and X-ray photoelectron spectroscopy), and molecular dynamics simulations were carried out. Urea had a positive effect on the adsorption of LMWD, whereas a competitive effect existed for the adsorption of HMWD. The dominant interactions among DON, urea, and clay minerals included H-bonding, ligand exchange, and cation exchange. The urea was preferentially adsorbed on clay minerals and formed a complex, which provided more adsorption sites to LMWD and only a few to HMWD. The presence of urea increased the retention of LMWD and decreased the retention of HMWD in clay minerals. The retention capacity of LMWD increased by 6.9%-12.8%, while that of HMWD decreased by 6.7%-53.1%. These findings suggest that LMWD tended to be trapped in soils, while HMWD was prone to be leached into groundwater, which can be used to evaluate the leaching of DON from soil to groundwater.

Uncovering the pharmacological mechanisms of Patchouli essential oil for treating ulcerative colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Pogostemonis Herba has long been used in traditional Chinese medicine to treat inflammatory disorders. Patchouli essential oil (PEO) is the primary component of Pogostemonis Herba, and it has been suggested to offer curative potential when applied to treat ulcerative colitis (UC). However, the pharmacological mechanisms of PEO for treating UC remain to be clarified. AIM OF THE STUDY: To elucidate the pharmacological mechanisms of PEO for treating UC. METHODS AND RESULTS: In the present study, transcriptomic and network pharmacology approaches were combined to clarify the mechanisms of PEO for treating UC. Our results reveal that rectal PEO administration in UC model mice significantly alleviated symptoms of UC. In addition, PEO effectively suppressed colonic inflammation and oxidative stress. Mechanistically, PEO can ameliorate UC mice by modulating gut microbiota, inhibiting inflammatory targets (OPTC, PTN, IFIT3, EGFR, and TLR4), and inhibiting the PI3K-AKT pathway. Next, the 11 potential bioactive components that play a role in PEO's anti-UC mechanism were identified, and the therapeutic efficacy of the pogostone (a bioactive component) in UC mice was partially validated. CONCLUSION: This study highlights the mechanisms through which PEO can treat UC, providing a rigorous scientific foundation for future efforts to develop and apply PEO for treating UC.

Hypotensive effect of potent angiotensin-I-converting enzyme inhibitory peptides from corn gluten meal hydrolysate: Gastrointestinal digestion and transepithelial transportation modifications.

The study examined the antihypertensive effect of peptides derived from pepsin-hydrolyzed corn gluten meal, namely KQLLGY and PPYPW, and their in silico gastrointestinal tract digested fragments, KQL and PPY, respectively. KQLLGY and PPYPW showed higher angiotensin I-converting enzyme (ACE)-inhibitory activity and lower ACE inhibition constant (Ki) values when compared to KQL and PPY. Only KQL showed a mild antihypertensive effect in spontaneously hypertensive rats with -7.83 and - 5.71 mmHg systolic and diastolic blood pressure values, respectively, after 8 h oral administration. During passage through Caco-2 cells, KQL was further degraded to QL, which had reduced ACE inhibitory activity. In addition, molecular dynamics revealed that the QL-ACE complex was less stable compared to the KQL-ACE. This study reveals that structural transformation during peptide permeation plays a vital role in attenuating antihypertensive effect of the ACE inhibitor peptide.

Molecular dynamics study on structural modulation and dyeing property optimization of meta-aramid in a DMSO/electrolyte system.

Meta-aramid (PMIA) fabrics are typically problematic to dye owing to their extremely crystalline structure and high compactness. Herein, Dimethyl sulfoxide (DMSO) and electrolyte as hydrogen bond regulators were selected to improve the dyeability of PIMA dyed with cationic dyes. The PMIA shows both high dyeing and mechanical properties as a result of the synergistic effect of DMSO and electrolyte in the system, which destructs hydrogen bonding networks and increase interaction energy density between dye molecules and PMIA, confirmed by a series of characterization and molecular dynamics simulations. In the DMSO/NaCl/PMIA system, while maintaining excellent mechanical (breaking strength and elongation at break of 24.6Mpa and 37.6 %, respectively) and thermal properties, PMIA not only obtained the best dyeability, increasing the Dye uptake from 20 % to 70.62 % and the K/S value from 2.92 to 18.02, but also achieved excellent colour fastness (fastness to dry and wet rubbing, fastness to light, and fastness to washing of 4-5, 3-4, 3-4 and 4-5, respectively). Simulated results and experimental data verified that the DMSO/NaCl system optimally synergizes hydrogen bond regulation for PMIA and achieves the best dyeing effects for cationic dyes, manifesting its great potential in the PMIA wearability area.

Electrospinning of cellulose nanocrystals; procedure and optimization.

Cellulose nanocrystals (CNCs) and cellulose microfibrils (CMFs) are promising materials with the potential to significantly enhance the mechanical properties of electrospun nanofibers. However, the crucial aspect of optimizing their integration into these nanofibers remains a challenge. In this work, we present a method to prepare and electrospin a cellulosic solution, aiming to overcome the existing challenges and realize the optimized incorporation of CNCs into nanofibers. The solution parameters of electrospinning were explored using a combined experimental and simulation (molecular dynamics) approach. Experimental results emphasize the impact of polymer solution concentration on fiber morphology, reinforcing the need for further optimization. Simulations highlight the intricate factors, including the molecular weight of cellulose acetate (CA) polymer chains, electrostatic fields, and humidity, that impact the alignment of CNCs and CMFs. Furthermore, efforts were made to study CNCs/CMFs alignment rate and quality optimization. It is predicted that pure CNCs benefit more from electrostatic alignment, while lower molecular weight CA enables better CNC/CMF alignment.

Self-assembly of mixed-linkage glucan hydrogels formed following EG16 digestion.

Mixed-linkage glucans are major components of grassy cell-walls and cereal endosperm. Recently identified plant endo-ß-glucanase from the EG16 family cleaves MLGs with strong specificity towards regions with at least four sequential ß(1,4)-linked glucose residues. This activity yields a low molecular-weight MLG with a repeating structure of ß(1,3)-linked cellotriose that gels rapidly at concentrations as low as 1.0 % w/v. To understand the gelation mechanism, we investigated the structure and behavior using rheology, microscopy, X-ray scattering, and molecular dynamics simulations. Upon digestion, the material's rheological behavior changes from typical polymeric material to a fibrillar network behavior seen for e.g. cellulose nanofibrils. Scanning electron microscopy and confocal microscopy verifies these changes in micro- and nanostructure. Small-angle X-ray scattering shows in-solution self-assembly of MLG through ~10 nm elemental structures. Wide-angle X-ray scattering data indicate that the polymer association is similar to cellulose II, with dominant scattering at d-spacing of 0.43 nm. Simulations of two interacting glucan chains show that ß(1,3)-linkages prevent the formation of tight helices that form between ß(1,4)-linked d-glucan chains, leading to weaker interactions and less ordered inter-chain assembly. Overall, these data indicate that digestion drives gelation not by enhancement of interactions driving self-assembly, but by elimination of unproductive interactions hindering self-assembly.

Construction of Coarse-Grained Molecular Dynamics Model of Nuclear Global Chromosomes Dynamics in Mammalian Cells.

Biomolecules contain various heterogeneities in their structures and local chemical properties, and their functions emerge through the dynamics encoded by these heterogeneities. Molecular dynamics model-based studies will greatly contribute to the elucidation of such chemical/mechanical structure-dynamics-function relationships and the mechanisms that generate them. Coarse-grained molecular dynamics models with appropriately designed nonuniform local interactions play an important role in considering the various phenomena caused by large molecular complexes consisting of various proteins and DNA such as nuclear chromosomes. Therefore, in this chapter, we will introduce a method for constructing a coarse-grained molecular dynamics model that simulates the global behavior of each chromosome in the nucleus of a mammalian cell containing many giant chromosomes.

Integrative Modeling of 3D Genome Organization by Bayesian Molecular Dynamics Simulations with Hi-C Metainference.

Polymer modeling has been playing an increasingly important role in complementing 3D genome experiments, both to aid their interpretation and to reveal the underlying molecular mechanisms. This chapter illustrates an application of Hi-C metainference, a Bayesian approach to explore the 3D organization of a target genomic region by integrating experimental contact frequencies into a prior model of chromatin. The method reconstructs the conformational ensemble of the target locus by combining molecular dynamics simulation and Monte Carlo sampling from the posterior probability distribution given the data. Using prior chromatin models at both 1 kb and nucleosome resolution, we apply this approach to a 30 kb locus of mouse embryonic stem cells consisting of two well-defined domains linking several gene promoters together. Retaining the advantages of both physics-based and data-driven strategies, Hi-C metainference can provide an experimentally consistent representation of the system while at the same time retaining molecular details necessary to derive physical insights.

Ion adsorption-enrichment effect and its driving mechanism for nano-dots lithography with SPM probe on water-soluble crystal surfaces.

HYPOTHESIS: Water-soluble KDP (KH2PO4) crystals possess excellent optical properties and are employed as frequency converters in clean fusion energy. To improve their performances, there is an immediate necessity to lithograph surface nano-patterns on them. Although the Scanning Probe Microscope (SPM) provides a promising way to achieve this purpose through the water menisci, the driving mechanisms of the lithographic behaviors have not yet been revealed. SIMULATIONS AND EXPERIMENTS: Multi-scale investigations are constructed to explore the underlying driving mechanisms. The SPM probe-induced ion diffusion-transport behaviors are investigated by molecular dynamics. The ion adsorption-enrichment mechanisms are revealed by 18 adsorption models via the ab initio. The SPM probe-induced self-assembly experiments are performed to prove the local heavy concentration. A comprehensive model is developed to describe the lithography mechanisms of the probe-induced self-assembly nano-dots on water-soluble substrates. FINDINGS: It is interestingly found that the KDP growth units (H2PO4-) exhibit obvious adsorption-enrichment effect at 3.16 Å from the probe surface, causing local heavy concentration. The H2PO4- would spontaneously adsorb onto the probe surface, which is dominated by the Si-O bonding reactions. The nano-dots with the height of 27 âˆ¼ 48 nm and diameter of 2.0 âˆ¼ 2.7 µm are lithographed on the KDP substrate. The proposed model further confirms that the lithography processes are driven by the solution supersaturation, solute diffusion, and surface free energy.

Transcriptomics changes of calcitonin gene-related peptide in mitigating lipopolysaccharide-induced septic cardiomyopathy.

Septic cardiomyopathy (SCM), a complication initiated by sepsis, presents a significant clinical challenge, leading to increased mortality rates. However, the mechanisms of SCM have not been fully uncovered. Our study involved analyzing RNA sequencing (RNA-seq) data from rat heart tissue, along with utilizing molecular docking and molecular dynamics (MD) simulations, to discover key targets and potential pharmacological actions of the calcitonin gene-related peptide (CGRP) against SCM. A lipopolysaccharide-induced SCM model was established in rats (LPS 10 mg/kg, intraperitoneal (i.p.)). Thereafter, the myocardial tissues from the three groups of rats (Ctrl group, LPS group, and CGRP group) (n = 5) were extracted and underwent RNA-seq, followed by bioinformatics analyses. The qPCR-validated hub targets potentially interacting with CGRP were identified. Following this, homology modeling was utilized to obtain the 3D structure of hub targets, and molecular docking was conducted to evaluate the interaction between CGRP and hub targets. MD simulations (300 ns) were performed to confirm the findings further. Our findings demonstrated that CGRP significantly lowered mortality in SCM rats. 633 DEGs were affected by LPS, contrasted with the Ctrl group. 96 DEGs were affected by CGRP compared to the LPS group. In total, ten fully annotated CGRP-triggered hub genes were obtained. The molecular docking and MD simulations indicate that the relationship between CGRP and eight hub genes is extremely strong. This research offers a thorough examination of the possible objectives and fundamental molecular processes of CGRP in combating SCM, laying the groundwork for investigating the potential protective mechanisms of CGRP against SCM.

Molecular dynamics investigation of epoxy resin adsorption mechanisms on clay surfaces and the mechanical properties of epoxy resin-clay.

The strength of natural clay can be improved with epoxy resins. However, nanoscale curing mechanisms remain poorly understood, which is essential for enhancing stability. In this study, molecular dynamics simulation was employed to calculate the quantity of interface hydrogen bonds, adsorption energy, radius of gyration, and mechanical properties of clay cured by diglycidyl ether of bisphenol-A epoxy resin (DGEBA), diglycidyl ether 4,4'-dihydroxy diphenyl sulfone (DGEDDS), and Aliphatic epoxidation of olefin resin (AEOR). Adsorption behavior and mechanical properties of the clay cured by three epoxy resins were investigated: (1) The chain structure of AEOR led to 18.2% more hydrogen bonds than DGEBA and 59.1% more than DGEDDS. (2) The simulated adsorption energies for DGEBA, DGEDDS, and AEOR with kaolinite were 92.59, 98.25, and 116.87 kcal·mol-1, respectively. (3) The bulk and shear modulus of kaolinite increased by 4.93% and 4.80% when using AEOR. The interface stability and mechanical properties of kaolinite were also improved through strong hydrogen bonds and high adsorption energy. (4) The improvement in Young's modulus of kaolinite was most significant with AEOR, followed by DGEDDS. AEOR excelled in the Z direction, while DGEDDS excelled in the X and Y directions. This research provided a theoretical foundation to effectively improve the properties of clay using epoxy resins.

Structure-based screening of FDA-approved drugs and molecular dynamics simulation to identify potential leukocyte antigen related protein (PTP-LAR) inhibitors.

Leukocyte antigen related protein (LAR), a member of the PTP family, has become a potential target for exploring therapeutic interventions for various complex diseases, including neurodegenerative diseases. The reuse of FDA-approved drugs offers a promising approach for rapidly identifying potential LAR inhibitors. In this study, we conducted a structure-based virtual screening of FDA-approved drugs from ZINC database and selected candidate compounds based on their binding affinity and interactions with LAR. Our research revealed that the candidate compound ZINC6716957 exhibited excellent binding affinity to the binding pocket of LAR, formed interactions with key residues at the active site, and demonstrated low toxicity. To further understand the binding dynamics and interaction mechanisms, the 100-ns molecular dynamics simulations were performed. Post-dynamics analyses (RMSD, RMSF, SASA, hydrogen bond, binding free energy and free energy landscape) indicated that the compound ZINC6716957 stabilized the structure of LAR and the residues (Tyr1355, Arg1431, Lys1433, Arg1528, Tyr1563 and Thr1567) played a vital role in stabilizing the conformational changes of protein. In conclusion, the identified compound ZINC6716957 possessed robust inhibitory activity on LAR and merited extensive research, potentially unleashing its significant therapeutic potential in the treatment of complex diseases, particularly neurodegenerative disorders.

Understanding Cu+2 binding with DNA: A molecular dynamics study comparing Cu2+ and Mg2+ binding to the Dickerson DNA.

Cu2+ ions led DNA damage by reactive oxygen species (ROS) is widely known biological phenomena. The ionic radii of Cu2+ and Mg2+ being similar, the binding of Cu2+ ions to DNA is expected to be similar to that of the Mg2+ ions. However, little is known how Cu2+ ions bind in different parts (phosphate, major and minor grooves) of a double-strand (ds) DNA, especially at atomic level. In the present study, we employ molecular dynamic (MD) simulations to investigate the binding of Cu2+ ions with the Dickerson DNA, a B-type dodecamer double stranded (ds) DNA. The binding characteristics of Cu2+ and Mg2+ ions with this dsDNA are compared to get an insight into the differences and similarities in binding behavior of both ions. Unlike Mg2+ ions, the first hydration shell of Cu2+ is found to be labile, thus it shows both direct and indirect binding with the dsDNA, i.e., binding through displacement of water from the hydration shell or through the hydration shell. Though the binding propensity of Cu2+ ions with dsDNA is observed relatively stronger, the binding order to phosphates, major groove, and minor groove is found qualitatively similar (phosphates > major groove > minor groove) for both ions. The study gives a deep understanding of Cu2+ binding to DNA, which could be helpful in rationalizing the Cu2+ led ROS-mediated DNA damage.

Thermal unfolding of alpha-lactalbumin at acidic pH: Insights from molecular dynamics simulations.

The transformation of globular proteins into fibrils passes through several stages, including the formation of partially expanded conformational states different from the native or fully unfolded forms. Here we used molecular dynamics simulations to characterize the thermal unfolding of alpha-lactalbumin on the microsecond timescale in the range of temperatures of 300-440 K. Comparative analysis of structural changes, mobility of different parts of protein, and pathways through the free energy landscape during the unfolding of alpha-lactalbumin at different temperatures reveals the existence of several intermediate states separated by small energy barriers. The lifetime of these intermediates depends on temperature and varies from nanoseconds to microseconds.

Exploring the competitive inhibition of α-glucosidase by citrus pectin enzymatic hydrolysate and its mechanism: An integrated experimental and simulation approach.

The endo-polygalacturonase D (PgaD) from Aspergillus niger JL15 was recombinantly expressed in Escherichia coli BL21, exhibiting an optimal activity at 55 °C and pH 4.0. Hydrolysis products of citrus pectin by recombinant PgaD included galacturonic acid (GalA), digalacturonic acid (GalA2), trigalacturonic acid (GalA3), and tetragalacturonic acid (GalA4). The hydrolysates exhibited significant antioxidant capacity and dose-dependent competitive inhibition of α-glucosidase. GalA2 and GalA3 acted as competitive inhibitors of α-glucosidase, with inhibition constant of 0.0589 mmol.L-1 and 0.6732 mmol.L-1, respectively. Molecular dynamics (MD) simulations revealed that both GalA2 and GalA3 penetrated the catalytic pocket of α-glucosidase and formed stable hydrogen bonds with key catalytic residues D352 and D215. The binding free energies of GalA2-α-glucosidase and GalA3-α-glucosidase complexes were - 10.3 ± 0.6 kcal·mol-1 and -10.8 ± 0.7 kcal·mol-1, respectively. These findings might offer new ideas for the development of α-glucosidase inhibitors sourced from citrus pectin, as well as enhance utilization of the renewable plant polysaccharide resources.

Integrated computational approaches for advancing antimicrobial peptide development.

The increasing prevalence of antimicrobial resistance has intensified the need for novel antimicrobial drugs. Antimicrobial peptides (AMPs) are promising alternative antibiotics due to their broad-spectrum activity and slower resistance development. However, the time-consuming, costly development and challenge of systematic optimization limit their translation into the clinic. Recently, integrating computational methods have led to breakthroughs in the precise design and optimization of AMPs, reduced resource consumption, and accelerated AMP development process. We highlight the application of these integrated approaches in AMP molecule discovery, optimization, and delivery and demonstrate the synergy of these strategies to fuel AMP development.

In silico screening and identifying phytoconstituents of Withania somnifera as potent inhibitors of BRCA1 mutants: A therapeutic against breast cancer.

Breast CAncer gene 1 (BRCA1) is an anti-oncogene that helps the cell repair damaged DNA and preserve genetic material. BRCA1 also acts as a cell growth suppressor and produces tumor suppressor gene (TSG) proteins, i.e., BRCA1 protein. Remarkably, BRCA1 mutations account for 90 % of hereditary breast cancer and a majority of hereditary ovarian cancer. Hence, we have considered three mutants of BRCA1 (R1699W, R1699Q, T1700A) in this study and adopted an in-silico approach to find the best possible phytochemical to inhibit these mutated proteins, enabling early breast cancer diagnosis. Perceiving the importance, many natural molecules from ancient medicinal plants are considered for molecular docking. Our findings suggest that though many molecules bind actively with the receptor's active site, the top three phytoconstituents (27-Deoxy-14-hydroxywithaferin A, Withacoagulin, Somniferanolide) of Withania somnifera, commonly known as Ashwagandha, have high binding affinities and suitable pharmacokinetic properties, making these natural compounds potential drug candidates. Further, molecular dynamics (MD) simulation and the binding free energy calculation show stability and thermodynamically favourable. We can, therefore, draw the conclusion that these lead compounds act as potential inhibitors against BRCA1. However, wet lab experiments and clinical trials are recommended to ascertain its efficacy, hence the development of novel BRCA1 inhibitors.

From Water Under Confinement to Understanding Life at Subzero Temperatures.

Water in confined geometries is highly relevant to biology, geology, and other fields where the function and properties of materials are significantly influenced by the presence and behavior of water in these environments. The structure and dynamics of confined water are strongly dependent on the confining geometry and its interaction with the interfaces. This review provides a brief overview of water under nano-sized hard and soft confinement, as well as water in living cells and in the hydration shells around biomolecules. Confined water exhibits distinct characteristics compared to bulk water, particularly in terms of nucleation, crystallization, molecular dynamics, and hydrogen bond network. In nano-sized confinements, water can remain in liquid state at extremely low temperatures (from -45 °C to -120 °C, at atmospheric pressure), offering insights into the fundamental physics of water and potentially enhancing our understanding of life in subzero temperature environments.

Highly cost-effective wheat starch-stearic acid complexes enabled by microwave processing: Structural properties, anti-digestion, and molecular dynamics simulation.

Microwave (MW) heating shows higher efficiency in preparing wheat starch-stearic acid (WS-SA) complexes than the traditional water bath (WB) heating method, while the detailed "time-energy-quality" evaluations and the potential anti-digestion mechanism of the MW-processed WS-SA remain further exploration. In this study, 95 % time cost and 73 % energy consumption were saved when using MW processing WS-SA, and the MW-processed complexes were verified to show significantly higher relative crystallinity, short-range ordered structure degree, thermal stability, complex index, and resistant starch content. Molecular dynamics (MD) simulation demonstrated that MW treatment notably facilitated the binding rate of amylose and SA molecules, generating a tight and stable helical structure through hydrogen bonds and van der Waals forces. Analyses of solvent-accessible surface area and water status cross-verified that the denser structure could endow the MW-processed complexes with higher resistance to water solvation effects and correspondingly reduce the water mobility for enzymatic hydrolysis reactions, ultimately making the MW-processed complexes more undigestible. This study provides a further understanding of the anti-digestion mechanisms of the MW-processed WS-SA from the molecular level, and it is expected that the current work could attract more concerns to the highly cost-effective MW heating method for processing starchy food.