MD Simulation Data Research Articles

Interactions of Li+ ions with NCS1: A potential mechanism of Li+ neuroprotective action against psychotic disorders

Li+ based drugs have been used for the treatment of psychiatric disorders due to their mood stabilizing role for decades. Recently, several studies reported the protective effect of Li+ against severe neuropathologies such as Parkinson's, Alzheimer's, and Huntington's disease. Surprisingly, despite a broad range of Li+ effects on neurological conditions, little is known about its molecular mechanism. In this study, we propose that neuronal calcium sensor 1 (NCS1), can be an effective molecular target for Li+ action. Here we show that the EF-hands in ApoNCS1 have submillimolar affinity for Li+ with Kd = 223 ± 19 μM. Li+ binding to ApoNCS1 quenches Trp emission intensity, suggesting distinct Trp sidechains environment in Li+NCS1 compared to ApoNCS1 and Ca2+NCS1. Li+ association also stabilizes the protein α-helical structure, in a similar way to Ca2+. Li+ association does not promote NCS1 dimerization. Association of Li+ increases NCS1 affinity for the D2R receptor binding peptide, in a similar way to Ca2+, however, the affinity of NCS1 for chlorpromazine is reduced with respect to Ca2+NCS1, possibly due to a decrease in solvent exposed hydrophobic area on the NCS1 surface in the presence of Li+. MD simulation data suggests that Li+ ions are coordinated by four oxygens from Asp and Glu sidechains and one carbonyl oxygen, in a similar way as reported previously for Li+ binding to DREAM. Overall, the data shows that Li+ binds to EF-hands of NCS1 and Li+NCS1 interactions may be involved in the potential neuroprotective role of Li+ against psychotic disorders.

Thermodynamic properties and structure of interfacial boundaries in nonionic fluids from the multilayer quasichemical model

The interfacial properties and structure of nonuniform fluids containing complex chainlike molecules and associating species are very much needed in a variety of different fields, including enhanced oil recovery, drug delivery, pharmacy, cosmetics, food processing, etc.Recently, we described the Multilayer Quasichemical Model (MQuM) of a nonuniform fluid that provides a remarkably detailed structural information, including the local concentration and orientation of functional groups of the molecules, the orientation profiles of the chemical bonds in molecular chains and the orientation profiles of the hydrogen bonds in the mixture.In this work, we focus on the description of thermodynamic properties with the aid of MQuM, including the interfacial tension and the profiles of normal and transverse pressures. Before proceeding to more complex systems, a test is performed through comparison with the previously known results from the Scheutjens-Fleer theory for the planar liquid–vapor interface and spherical droplet in one-component fluid of nonpolar monomeric molecules. The model is applied then for planar interfaces between the liquid phases in mixtures of water with n-alkanes of different chain length and for spherical drops in model systems that contain an associating solvent, a nonpolar chain and a nonionic amphiphile. Our theoretical results are compared with experiment, predictions from iSAFT and MD simulation data from the literature. For the spherical droplets, we discuss the model description of the dependence of the interfacial tension on the curvature and estimate the Tolman length. For the planar interface between the equilibrium liquid phases in water – n-alkane mixtures, the interfacial tensions predicted from the model are in good agreement with experiment.

Exploring marine-derived bioactive compounds for dual inhibition of Pseudomonas aeruginosa LpxA and LpxD: integrated bioinformatics and cheminformatics approaches.

Pseudomonas aeruginosa can cause serious nosocomial infections. Targeting the biosynthesis of Lipid A, a major structural domain of lipopolysaccharide (LPS) in P. aeruginosa has emerged as a valuable strategy for developing novel therapeutic agents. The biosynthesis of Lipid A involves the activation of homolog enzymes including LpxA and LpxD. LpxA enzyme facilitates the transfer of R-3-hydroxydecanoic fatty acid to uridine diphosphate N-acetylglucosamine in the first step. While LPxD is accountable in third step, wherein R-3-hydroxydodecanoate is transferred to the 2' amine of UDP-3-O-(3-hydroxydecanoyl) utilizing an ACP donor. The exploration of LpxA and LpxD has been largely neglected, as no specific small-molecule inhibitors have been identified, thus far, except for peptide inhibitors. Here, we report the identification of potential dual inhibitors of the lipid A biosynthesis pathway that target both the LpxA and LpxD enzymes as novel antibiotic agents. Among the virtually screened 32,000 marine bioactive compounds Oscillatoxin A, NCI60_041046, and LTS0192263 exhibited optimal docking interactions with LpxA and LpxD, respectively. MD simulation and MMPBSA data showcased stable interactions between selected marine products and LpxA/LpxD. FMO analysis showed that Oscillatoxin A and NCI60_041046 are the most chemically active molecules. MEP analysis data highlighted the possible electrophilic and nucleophilic distribution zones present in the structure. In addition, these bioactive molecules showed acceptable ADMET profiles. These data confirmed that Oscillatoxin A, NCI60_041046, and LTS0192263 could serve as seeds for the development of potential therapeutics to combat P. aeruginosa infection.

Flavonoids as potential KRAS inhibitors: DFT, molecular docking, molecular dynamics simulation and ADMET analyses

KRAS mutations linked with cancer. Flavonoids were docked against KRAS G12C and G12D receptors. Abyssinone III, alpha naphthoflavone, beta naphthoflavone, abyssinone I, abyssinone II and beta naphthoflavone, genistin, daidzin showed good docking scores against KRAS G12C and G12D receptors, respectively. The MD simulation data revealed that Rg, RMSD, RMSF, and SASA values were within acceptable limits. Alpha and beta naphthoflavone showed good binding energies with KRAS G12C and G12D receptors. DFT and MEP analysis highlighted the nucleophilic and electrophilic zones of best-docked flavonoids. A novel avenue for the control of KRAS G12C and G12D mutations is made possible by flavonoids.

An empirical experimental observations and MD simulation data-based model for the material properties of confined fluids in nano/Angstrom size tubes

Abstract The transport of fluids in nanometer and Angstrom-sized pores has gotten much attention because of its potential uses in nanotechnology, energy storage, and healthcare sectors. Understanding the distinct material properties of fluids in such close confinement is critical for enhancing their performance in various applications. These properties dictate the fluid’s behavior and play a crucial role in determining flow dynamics, transport processes, and, ultimately, the performance of nanoscale devices. Remarkably, many researchers observed that the size of the geometry, such as the diameter of the confining nanotube, exerts a profound and intriguing influence on the material properties of nanoconfined fluids, including on the critical parameters such as density, viscosity, and slip length. Many researchers tried to model these material properties: viscosity η, density ρ, and slip λ using various models with many dependencies on the tube diameter. It is somewhat confusing and tough to decide which model is appropriate and needs to be incorporated in the numerical simulation. In this paper, we tried to propose a simple single equation for each nano confined material property such as for density ρ ( D ) / ρ o = a + b / ( D − c ) n , viscosity η ( D ) / η o = a + b / ( D − c ) n , and the slip length λ(D) = λ 1 D e −n D + λ o (where a, b, c, n, λ 1, λ o are the free fitting parameters). We model a wealth of previous experimental and MD simulation data from the literature using our proposed model for each material property of nanoconfined fluids at the nanometer and Angstrom scales. Our single proposed equation effectively captures and models all the data, even though many different models have been employed in the existing literature to describe the same material property. Our proposed model exhibits exceptional agreement with multiple independent datasets from the experimental observations and molecular dynamics simulations. Additionally, the model possesses the advantageous properties of continuity and a continuous derivative, so the proposed model is well-suited for integration into numerical simulations. Further, the proposed models also obey the far boundary conditions, i.e., when tube diameter D ⟹ ∞, the material properties tend to the bulk properties of the fluid. Due to the models’ simplicity, smooth, and generic nature, this heuristic model holds promise to apply in simulations to design and optimize nanoscale devices.

In-Silico Evaluation of Deoxyvasicinone and Semi Synthetic derivatives of Justicia adhatoda against Coronavirus

Novel coronavirus disease (COVID-19) is the major health crisis in the world. World Health Organization has declared COVID-19 as a global pandemic. There are no effective drugs to treat COVID-19 infection. Some drugs include remdesivir, umifenovir, favipiravir, lopinavir/ ritonavir, ribavirin, hydroxychloroquine, etc are used to treat this disease. There is an urgent need for public health measures to implement preventive approaches to control severe COVID-19 disease. Justica adhatoda is a well-known plant drug in Ayurvedic and Unani medicines. Various phytochemical constituents have been isolated from J. adhatoda which possesses activities like antitussive, abortifacient, antimicrobial, cardiovascular protection, anticholinesterase, anti-inflammatory and other important activities. The alkaloids from leaf extracts of J. adhatoda possess anti-viral activity. Molecular docking interaction study against 6W63 showed that molecule 4d showed maximum docking interaction with dock score of (-) 8.1 kcal/mol. MD simulation data reflected the stable ligand-receptor interaction. Maximum and minimum energy gap were showed by 7 and 4d, respectively. The order of stability of the synthesized molecules were 4d>2>3>5>4c>4a>4b>1>6>7. The order of ionization potential and electron affinity of the synthesized molecules were 3>4c>4b>4a>1>6>7>4d>5>2. These data confirmed that molecule 4d would be a boon for society.

Unraveling the Aurora kinase A and Epstein-Barr nuclear antigen 1 axis in Epstein Barr virus associated gastric cancer

Aurora kinase A (AURKA) is one of the crucial cell cycle regulators associated with gastric cancer. Here, we explored Epstein Barr Virus-induced gastric cancer progression through EBV protein EBNA1 with AURKA. We found that EBV infection enhanced cell proliferation and migration of AGS cells and upregulation of AURKA levels. AURKA knockdown markedly reduced the proliferation and migration of the AGS cells even with EBV infection. Moreover, MD-simulation data deciphered the probable connection between EBNA1 and AURKA. The in-vitro analysis through the transcript and protein expression showed that AURKA knockdown reduces the expression of EBNA1. Moreover, EBNA1 alone can enhance AURKA protein expression in AGS cells. Co-immunoprecipitation and NMR analysis between AURKA and EBNA1 depicts the interaction between two proteins. In addition, AURKA knockdown promotes apoptosis in EBV-infected AGS cells through cleavage of Caspase-3, -9, and PARP1. This study demonstrates that EBV oncogenic modulators EBNA1 possibly modulate AURKA in EBV-mediated gastric cancer progression.

Crystal plasticity model of BCC metals from large-scale MD simulations

Accurate crystal plasticity models that faithfully capture the behavior of single crystals under a wide range of loading conditions, such as loading direction, strain rate, and temperature, are still lacking. Here we introduce a novel approach in which a crystal plasticity (CP) model is informed directly from and calibrated to large-scale quantum-accurate MD simulations in which single crystal BCC Ta serves as a testbed material. By analyzing our large set of MD simulations several key insights are obtained leading us to modify constitutive assumptions in order to address deficiencies of existing CP models. Importantly, we observe that the standard notion of fixed slip systems – pairs of slip directions and slip planes – is inadequate for describing high-rate plasticity in BCC tantalum at room temperature. Instead, pencil glide defined as dislocation motion in the maximum resolved shear stress planes (MRSSP) of each Burgers vector is fully consistent with our MD simulation data while providing significant simplifications of the constitutive relations. Our resulting new CP model closely matches the behavior of single crystals observed in high-rate MD simulations while being fully consistent with lower rate experimental results.

Immunoinformatics and MD-simulation data suggest that Omicron spike epitopes are more interacting to IgG via better MHC recognition than Delta variant

BackgroundRecently, in Nov 2021, in South Africa, the SARS CoV-2 variant Omicron was found to be highly infectious and transmissible but with the least fatality. It occupies the nasopharynx-oropharynx and easily spreads. The epidemiological data/reports suggest that several vaccines failed to neutralize Omicron. It has a large number of spike mutations and the RNA/protein vaccines were developed from its predecessors that may justify its escape in most neutralization reactions. Its lower immuno-suppression/cytokine-storming/inflammatory-response effects need exploration. ObjectivesIn the current study, we attempted to delineate the comparative interaction of different variants’ spikes with multiple recognition sites on IgG and HLA-typing of MHC class and I and II. MethodsAll SARS-CoV-2 spike-proteins/human-IgG/MHC-I & II were obtained from the NCBI/ PDB/GISAID database. Initial 3D-structures of the unavailable proteins were constructed by Homology-Modeling (Swissmodel-Expasy) and optimized (PROCHECK). Molecular-docking of spike-IgG/spike- I & MHC-II was performed (HADDOCK2.4/HawkDock) with active-residue screening (CPORT). Antigenicity of epitopes was determined (Vaxigen v2.0-server) and the epitope-model prepared (PEP-FOLD3-server). The binding-affinity/biological-interfaces/visualize were performed (PRODIGY-PyMOL2). We also examined the genesis of feasible transition pathways of functional docked complexes (iMODs) of MHC with different epitopes and antibodies of IgG with different variants. Further, Molecular-Dynamic-Simulation was performed by GROMACS 2023.1 software package. The MD-simulation was run with 100 ns (300 k-heating/1-atm pressure). ResultsSurface-area with interactomes, H-bonding and polar/non-polar bonding were the highest in Omicron spike-IgG interaction. Unlike other variants, both the L and H chains of at least three different recognition sites of IgG interact with the N-terminal and C-terminal RBD of the S1-portion and partially bind to S2. In other cases, binding was observed in either NTD or CTD with a lesser number of bonding-interactomes, especially in Delta spike-Ab interaction. In the case of MHC class-I & II, the highest binding affinity/surface was noticed by Omicron and least by the Delta variant. The MD simulation data of lower RMSD values of the Delta and Omicron variants indicate improved structural stability and less departure from the initial conformation. Better binding to the IgG and MHC molecules explains Omicron’s little ability in immune invasion.

A novel missense compound heterozygous variant in TLR1 gene is associated with susceptibility to rheumatoid arthritis - structural perspective and functional annotations.

Besides human leukocyte antigen (HLA-DRB1) locus, more than 100 loci across the genome have been identified and linked with the onset, expression and/or progression of rheumatoid arthritis (RA). However, there are still grey areas in our understanding of the key genetic contributors of the disease, particularly in familial cases. In the present study, we have performed the whole exome sequencing (WES) of RA patients from two consanguineous families of Pakistan in a quest to identify novel, high-impact, RA-susceptibility genetic variants. Through stepwise filtering, around 17,000 variants (common in the affected members) were recognized, out of which 2651 were predicted to be deleterious. Of these, 196 had direct relevance to RA. When selected for homozygous recessive mode of inheritance, two novel pathogenic variants (c.1324T>C, p.Cys442→Arg442; c.2036T>C, p.Ile679→Thr679) in the TLR1 gene displayed the role of compound heterozygosity in modulating the phenotypic expression and penetrance of RA. The structural and functional consequences of the TLR1 missense single nucleotide mutations (Cys442→Arg442; Ile679→Thr679) were evaluated through molecular dynamic simulation (MDS) studies. Analysis showed domain's rigidification, conferring stability to mutant TLR1-TIR/TIRAP-TIR complex with concomitant increase in molecular interactions with pro-inflammatory cytokines, compared to the wild-type conformation. Gene co-expression network analysis highlighted interlinked partnering genes along with interleukin-6 production of TLR1 (corrected p-value 2.98e-4) and acetylcholine receptor activity of CHRNG (corrected p-value 6.12e-2) as highly enriched associated functions. The results, validated through case-control study subjects, suggested that the variants identified through WES and confirmed through Sanger sequencing and MDS are the novel disease variants and are likely to confer RA-susceptibility, independently and/or in a family-specific context. Key Points • Exploration of population based/ethno-specific big data is imperative to identify novel causal variants of RA. • Two new deleterious missense mutations in mutational hotspot exon 4 of TLR1 gene have been identified in Pakistani RA patients. • MD simulation data provides evidence for domain's rigidification, conferring stability to mutant TLR1-TIR/TIRAP-TIR complex, with concomitant increase in production of pro-inflammatory cytokines, thus adding to the onset/erosive outcome of RA.

Establishing the Role of Iridoids as Potential Kirsten Rat Sarcoma Viral Oncogene Homolog G12C Inhibitors Using Molecular Docking; Molecular Docking Simulation; Molecular Mechanics Poisson-Boltzmann Surface Area; Frontier Molecular Orbital Theory; Molecular Electrostatic Potential; and Absorption, Distribution, Metabolism, Excretion, and Toxicity Analysis.

The RAS gene family is one of the most frequently mutated oncogenes in human cancers. In KRAS, mutations of G12D and G12C are common. Here, 52 iridoids were selected and docked against 8AFB (KRAS G12C receptor) using Sotorasib as the standard. As per the docking interaction data, 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester (dock score: -9.9 kcal/mol), 6'-O-trans-para-coumaroyl geniposidic acid (dock score: -9.6 kcal/mol), 6-O-trans-cinnamoyl-secologanoside (dock score: -9.5 kcal/mol), Loganic acid 6'-O-beta-d-glucoside (dock score: -9.5 kcal/mol), 10-O-succinoylgeniposide (dock score: -9.4), Loganic acid (dock score: -9.4 kcal/mol), and Amphicoside (dock score: -9.2 kcal/mol) showed higher dock scores than standard Sotorasib (dock score: -9.1 kcal/mol). These common amino acid residues between iridoids and complexed ligands confirmed that all the iridoids perfectly docked within the receptor's active site. The 100 ns MD simulation data showed that RMSD, RMSF, radius of gyration, and SASA values were within range, with greater numbers of hydrogen bond donors and acceptors. MM/PBSA analysis showed maximum binding energy values of -7309 kJ/mol for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester. FMO analysis showed that 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester was the most likely chemically reactive molecule. MEP analysis data highlighted the possible electrophilic and nucleophilic attack regions of the best-docked iridoids. Of all the best-docked iridoids, Loganic acid passed Lipinski, Pfizer, and GSK filters with a similar toxicity profile to Sotorasib. Thus, if we consider these iridoids to be KRAS G12C inhibitors, they will be a boon to mankind.

Lactiplantibacillus plantarum and Saussurea costus as Therapeutic Agents against a Diabetic Rat Model-Approaches to Investigate Pharmacophore Modeling of Human IkB Kinase and Molecular Interaction with Dehydrocostus Lactone of Saussurea costus.

Lactic acid bacteria is well-known as a vital strategy to alleviate or prevent diabetes. Similarly, the plant Saussurea costus (Falc) Lipsch is a preventive power against diabetes. Here, we aimed to determine whether lactic acid bacteria or Saussurea costus is more effective in treating a diabetic rat model in a comparative study manner. An in vivo experiment was conducted to test the therapeutic activity of Lactiplantibacillus plantarum (MW719476.1) and S. costus plants against an alloxan-induced diabetic rat model. Molecular, biochemical, and histological analyses were investigated to evaluate the therapeutic characteristics of different treatments. The high dose of S. costus revealed the best downregulated expression for the IKBKB, IKBKG, NfkB1, IL-17A, IL-6, IL-17F, IL-1β, TNF-α, TRAF6, and MAPK genes compared to Lactiplantibacillus plantarum and the control groups. The downregulation of IKBKB by S. costus could be attributed to dehydrocostus lactone as an active compound with proposed antidiabetic activity. So, we performed another pharmacophore modeling analysis to test the possible interaction between human IkB kinase beta protein and dehydrocostus lactone as an antidiabetic drug. Molecular docking and MD simulation data confirmed the interaction between human IkB kinase beta protein and dehydrocostus lactone as a possible drug. The target genes are important in regulating type 2 diabetes mellitus signaling, lipid and atherosclerosis signaling, NF-κB signaling, and IL-17 signaling pathways. In conclusion, the S. costus plant could be a promising source of novel therapeutic agents for treating diabetes and its complications. Dehydrocostus lactone caused the ameliorative effect of S. costus by its interaction with human IkB kinase beta protein. Further, future studies could be conducted to find the clinical efficacy of dehydrocostus lactone.

Nature-inspired synthetic oligourea foldamer channels allow water transport with high salt rejection

•Synthetic, self-assembling, helical oligourea foldamers form artificial water channels •ssNMR, MD simulation, and cryo-EM data show proper insertion of foldamers into liposomes •Water-selective channels are formed by oligomerization of the amphipathic foldamers •4.8 Å hydrophilic pore is present in X-ray crystal structure of foldamer H2OC1 Biomimetic membranes incorporating artificial water channels (AWCs) are being developed for industrial water purification. Designing AWCs to achieve high water permeation with salt rejection is a challenge. We designed and synthesized oligourea foldamers, which form predictable helical structures that can be used to create biomimetic porin-like architectures. Two of these foldamers (H2OC1 and H2OC2) allow superior water permeability and almost total salt rejection across lipid membranes. Solid-state NMR, cryo-EM, and molecular dynamics analyses suggest proper insertion of foldamers into lipid vesicles. The H2OC1 crystal structure shows hydrophilic pores of diameters 4.8 and 6.4 Å. The oligourea helices pack together by hydrophobic and salt bridge interactions to build two channel-like assemblies. Besides their proteolytic stability and microbial resistance, the sequence of foldamers can be tailored to regulate selectivity. The ease of designing, synthesizing, and purifying oligourea foldamers is an added advantage. Our findings can help to develop novel AWCs for water purification applications. Biomimetic membranes incorporating artificial water channels (AWCs) are being developed for industrial water purification. Designing AWCs to achieve high water permeation with salt rejection is a challenge. We designed and synthesized oligourea foldamers, which form predictable helical structures that can be used to create biomimetic porin-like architectures. Two of these foldamers (H2OC1 and H2OC2) allow superior water permeability and almost total salt rejection across lipid membranes. Solid-state NMR, cryo-EM, and molecular dynamics analyses suggest proper insertion of foldamers into lipid vesicles. The H2OC1 crystal structure shows hydrophilic pores of diameters 4.8 and 6.4 Å. The oligourea helices pack together by hydrophobic and salt bridge interactions to build two channel-like assemblies. Besides their proteolytic stability and microbial resistance, the sequence of foldamers can be tailored to regulate selectivity. The ease of designing, synthesizing, and purifying oligourea foldamers is an added advantage. Our findings can help to develop novel AWCs for water purification applications.

Peganum harmala active compounds as potent inhibitors of Pseudomonas syringae virulent effectors. In silico study

Pseudomonas syringae (P syringae) is a group of bacterial foliar pathogens with a vast geographic distribution and large range of host plant species. In the present study, the effect of active compounds from Peganum harmala medicinal plant were analysed in silico on four P syringae virulent effectors. The docking results reveal that Harmalol, Harmaline and Vulgarone B molecules are the best docked phytochemicals with high binding affinities and strong intermolecular interactions better than those observed for Kanamycin, Spectinomycin and Streptomycin antibiotics with the four targeted virulent proteins. In addition Thymol ligand showed ability to bind firmly the 4RSX active site. The MD simulation data validated the docking results and confirmed the stability of complexes during 100 ns of simulation. In this work we proved through an in silico study that Harmaline, Harmalol, Vulgarone B and Thymol from Peganum harmala could be considerated as potential inhibitors of P syringae main effectors and could be used as anti-bacterial candidates against this phytopathogen.

Repurposing of drug molecules from FDA database against Hepatitis C virus E2 protein using ensemble docking approach.

Hepatitis C virus, a member of the Flaviviridae family and genus Hepacivirus, is an enveloped, positively single stranded RNA virus. Its surface consists of a heterodimer of E1 and E2 proteins which play a crucial role in receptor binding and membrane fusion. In this study we have used in silico virtual screening by utilizing ensemble docking on the approved drugs. These drugs can bind with high efficiency to the 36 prominent conformations of the CD81 binding site clustered from a total of 3µs MD simulation data on the E2 protein. We started with 9213 compounds from the FDA list of drugs and progressively came down to 5 compounds which have been seen to bind with very high efficiency to not only all the conformations but also the two predicted druggable pockets that encompass the CD81 binding site. MM/PBSA binding energy calculations also point to the highly stable interaction of the compounds to the E2 protein. This study may in future broaden the arsenal of therapeutics for use against HCV infection and lead to more effective care against the virus.

Phloretin and phlorizin mitigates inflammatory stress and alleviate adipose and hepatic insulin resistance by abrogating PPARγ S273-Cdk5 interaction in type 2 diabetic mice

AimsThe rising prevalence of type 2 diabetes mellitus (T2DM) and accompanying insulin resistance is alarming globally. Natural and synthetic agonists of PPARγ are potentially attractive candidates for diabetics and are known to efficiently reverse adipose and hepatic insulin resistance, but related side effects and escalating costs are the causes of concern. Therefore, targeting PPARγ with natural ligands is advantageous and promising approach for the better management of T2DM. The present research aimed to assess the antidiabetic potential of phenolics Phloretin (PTN) and Phlorizin (PZN) in type 2 diabetic mice. Main methodsIn silico docking was performed to check the effect of PTN and PZN on PPARγ S273-Cdk5 interactions. The docking results were further validated in preclinical settings by utilizing a mice model of high fat diet-induced T2DM. Key findingsComputational docking and further MD-simulation data revealed that PTN and PZN inhibited the activation of Cdk5, thereby blocking the phosphorylation of PPARγ. Our in vivo results further demonstrated that PTN and PZN administration significantly improved the secretory functions of adipocytes by increasing adiponectin and reducing inflammatory cytokine levels, which ultimately reduced the hyperglycaemic index. Additionally, combined treatment of PTN and PZN decreased in vivo adipocyte expansion and increased Glut4 expression in adipose tissues. Furthermore, PTN and PZN treatment reduced hepatic insulin resistance by modulating lipid metabolism and inflammatory markers. SignificanceIn summary, our findings strongly imply that PTN and PZN are candidates as nutraceuticals in the management of comorbidities related to diabetes and its complications.

APL@voro-interactive visualization and analysis of cell membrane simulations.

Molecular dynamics (MD) simulations of cell membranes allow for a better understanding of complex processes such as changing membrane dynamics, lipid rafts and the incorporation/passing of macromolecules into/through membranes. To explore and understand cell membrane compositions, dynamics and processes, visual analytics can help to interpret MD simulation data. APL@Voro is a software for the interactive visualization and analysis of cell membrane simulations. Here, we present the new APL@Voro, which has been continuously developed since its initial release in 2013. We discuss newly implemented algorithms, methodologies and features, such as the interactive comparison of related simulations and methods to assign lipids to either the upper or lower leaflet. The current open-source version of APL@Voro can be downloaded from http://aplvoro.com.

MD simulation data for the publication "How Carvedilol activates β2 adrenergic receptors"

MD simulation data for the publication "How Carvedilol activates β2 adrenergic receptors"

5-HT3 Receptor MX Helix Contributes to Receptor Function.

5-HT3 receptors are members of the family of pentameric ligand-gated ion channels. Each subunit has an extracellular, transmembrane, and intracellular domain. Only part of the intracellular domain structure has been solved, revealing it contains two α-helical segments; one, the MA helix, is an extension of M4, while the other, the MX helix, is formed from residues located close to the end of M3. This MX helix is in distinct locations in open and closed receptor structures, suggesting it may play a role in function. Here, we explore this hypothesis using functional responses of Ala-substituted mutant receptors expressed in HEK293 cells. The data show altering many of the MX residues results in a small decrease in EC50 (up to 5-fold), although in one (H232A) this is increased. Radiolabeled ligand binding on selected mutants showed no change in binding affinity, indicating an effect on gating and not binding. In addition, five mutations (P316A, V317A, P318A, D319A, and H323A) initially resulted in nonfunctional receptors, but the function could be rescued by coexpression with a chaperone protein, suggesting a likely role in assembly or folding. Examination of previously obtained MD simulation data shows that the extent of MX encompassed by membrane lipids differs considerably in the open and closed structures, suggesting that lipid–protein interactions in this region could have a major effect on channel opening propensity. We conclude that the MX helix can modulate the function of the receptor and propose that its interactions with membrane lipids play a major role in this.

Immunoinformatic paradigm predicts macrophage and T-cells epitope responses against globally conserved spike fragments of SARS CoV-2 for universal vaccination

BackgroundDifferent quickly-developed vaccines are introduced against COVID-19 with inconclusive results especially against some recent variants. Eventually, somewhere COVID-19 cases decline and in some countries it revived with some new mutant-variants (i.e. D614G, Delta and Omicron). ObjectivesProposing a universal vaccination strategy by screening globally-conserved SARS-CoV-2 spike-epitopes. MethodsPresently, several conserved (186-countries) sequences including multiple-variants (ClustalX2) epitopic-regions (SVMTriP and IEDB) and in-silico mutants of SARS-CoV-2 spike-protein-fragments (Cut1-4) were screened for their stability against proteases, antigenicity (VaxiJen V2.0 and for glycosylation effects NetOGlyc-NetNGlyc), MHCI/II reactivity (IEDB-TOOLS) and CD4+ responses by molecular-docking (Haddock2.4/PatchDock). We also examined Molecular-Dynamic-Simulation (myPresto verson-5) of MHC-II 3LQZ with 3-Cuts and T-cell 2-molecules (1KGC/4JRX) with SM3-Cut. The MD-simulation was run with 5000-cycles after 300 k-heating/1-atm pressure adjustment for the system-equilibration. Finally, 1000 fs production was run. ResultsThe cut4-mutant (SRLFRKSNLKPFERD) showed the highest combined-score 48.23548 and Immunogenicity-Score of 92.0887. The core-sequence SRLFRKSNL showed the highest Median-Percentile-Rank (7-HLA-allele) of 19. CD4+ immunogenicity also confirms the representation of the CUT4TM2 epitope SRLFRKSNL by MHC Class II. The epitope YNYKYRLFR from CUT4 showed an IC50 of ∼30 nM with allele HLA-DRB1*11:01 and HLA-DRB5*01:01 with plenty H-bonding. Cut4 double-mutants strongly interact with the exposed T-cell surface and are facilitated by its receptors. The MD-simulation data suggest that TM2 has a maximum RMSD value of 1.7 Å, DM2 is at 1.55 Å and SM3 is at 1.5 Å. These variations correspond to structural adjustments and involve binding/unbinding chemical interactions. The RMSD plot shows that 1KGC T-cell molecule is at 2.2 Å and the 4JRX is at 1.2 Å, which increases with the simulation time. ConclusionsScreening of conserved SARS-CoV-2 spike fragments helps to find the most stable antigenic-determinant which with some mutations showed better antigenicity. Further studies are necessary to develop global vaccination strategies against COVID-19.