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Journal of Molecular Graphics & Modelling

Alicja Nowaczyk, Łukasz Fijałkowski, Paula Zaręba, Kinga Sałat
Inhibition of 4-aminobutanoic acid (GABA) uptake is a strategy for enhancing GABA transmission. The utility of this approach is demonstrated by the successful development of such agents for the treatment of epilepsy and pain. Existing reports on acute brain slice preparations indicate the intersecting of complementary channels and receptors sets between astrocytes and neurons cells. Thorough analysis of astroglial cells by means of molecular and functional studies demonstrated their active modulatory role in intercellular communication...
September 8, 2018: Journal of Molecular Graphics & Modelling
Piyusha P Pagare, Huiqun Wang, Xiang-Yang Wang, Yan Zhang
Glucose Regulated Protein 170 (GRP170), also called Oxygen Regulated Protein 150 (ORP150), is a major molecular chaperone resident in the endoplasmic reticulum (ER). It belongs to the heat shock protein (HSP70) super family and can be induced by conditions such as hypoxia, ischemia and interferences in calcium homeostasis. It was recently reported that GRP170 may act as a nucleotide exchange factor (NEF) for GRP78 or binding immunoglobulin protein (BiP), and the ER canonical HSP70. However, little is known about the mechanism underlying its NEF activity...
September 6, 2018: Journal of Molecular Graphics & Modelling
Ryuhei Harada, Yasuteru Shigeta
Parallel cascade selection molecular dynamics (PaCS-MD) is a conformational sampling method for generating transition pathways from a given reactant to a product. In PaCS-MD, initial structures relevant to conformational transitions of proteins are selected and resampled by short-time MD simulations. As a general reaction coordinate, a root-mean-square deviation measured from the product (RMSD) is employed to rank the resampled configurations. Quantitatively, n initial structures are randomly selected from among the top X % of highly ranked configurations and resampled again...
September 5, 2018: Journal of Molecular Graphics & Modelling
Sneha Rai, Pallavi Mohanty, Sonika Bhatnagar
PH domains mediate interactions involved in cell signaling, intracellular membrane transport regulation and cytoskeleton organization. Some PH domains bind phosphoinositides with different affinity and specificity. The two novel PLCη (1 and 2) possess an N-terminal PH domain (PHη1 and PHη2 respectively) that has been implicated in membrane association and induction of PLC activity. Understanding of the structure and dynamics is crucial for future modulation of lipid-protein interactions in PHη1, PHη2 and other PH domains...
August 29, 2018: Journal of Molecular Graphics & Modelling
Mehreen Zaka, Bilal Haider Abbasi, Serdar Durdagi
Tumor necrosis factor alpha (TNFα) is a homotrimer protein that plays a pivotal role for critical immune functions, including infection, inflammation and antitumor responses. It also plays a primary role in autoimmune diseases like rheumatoid arthritis (RA). So far, only biological therapeutics like infliximab, etanercept, and adalimumab are available as treatment of inflammatory diseases. They directly bind to TNFα and interrupt its binding to its receptor protein tumor necrosis factor receptor (TNFR). However, they may also cause serious side effects such as activating an autoimmune anti-antibody response or the weakening of the body's immune defenses...
August 24, 2018: Journal of Molecular Graphics & Modelling
Aarti Anantram, Madhura Janve, Mariam Degani, Rekha Singhal, Harish Kundaikar
Iron transport through the duodenum is regulated by carrier proteins, one of which is the ubiquitously distributed divalent metal transporter (DMT1) which is responsible for the uptake of iron across the apical surface of the duodenal enterocyte. The crystallographic structure of Staphylococcus capitis divalent metal ion transporter (ScaDMT1) was obtained and it was used as a template for the construction of a homology model of human divalent metal transporter (hDMT1). The binding site for hDMT1 was determined by using SiteMap as well as molecular docking studies on ScaDMT1...
August 16, 2018: Journal of Molecular Graphics & Modelling
Jakub Kollar, Vladimir Frecer
Inhibitors of histone deacetylase superfamily (HDAC), which induce cell cycle arrest, trigger cell death and reduce angiogenesis appear as promising anti-cancer drugs targeting the epigenetic regulation of gene expression. Approved HDAC inhibitors were found effective against haematological and solid malignancies, other HDACIs are currently in clinical trials for the treatment of neurological diseases or immune disorders. Among those, diarylcyclopropane hydroxamic acids (DCHA) were found to be potent and selective inhibitors of the class IIa HDACs, specifically HDAC4, a pharmacological target for the treatment of Huntington's disease and muscular atrophy...
August 16, 2018: Journal of Molecular Graphics & Modelling
Zoya Khalid, Osman Ugur Sezerman
The Drug often binds to more than one targets defined as polypharmacology, one application of which is drug repurposing also referred as drug repositioning or therapeutic switching. The traditional drug discovery and development is a high-priced and tedious process, thus making drug repurposing a popular alternate strategy. We proposed an integrative method based on similarity scheme that predicts approved and novel Drug targets with new disease associations. We combined PPI, biological pathways, binding site structural similarities and disease-disease similarity measures...
August 14, 2018: Journal of Molecular Graphics & Modelling
Ali Ghiami-Shomami, Bahram Ghalami-Choobar, Yasuteru Shigeta
In this study, the structural and redox properties of a novel ferrocene derivative in dichlomethane solvent were investigated. For this aim, various exchange-correlation functionals and basis sets in gas phase with different continuum solvation models and cavities in liquid phase were applied. The results indicated that UM06/6-31++G(d,p)/SDD level of theory successfully calculated bond lengths and angles with MADs = 0.02 Å and 0.78 deg., respectively. Also, its combination with CPCM-Pauling-UHF/6-31+G(d)/SDD level of theory in liquid phase effectively computed the redox potential with 0...
August 7, 2018: Journal of Molecular Graphics & Modelling
Rui-Juan Niu, Qing-Chuan Zheng, Hong-Xing Zhang
As one of the first-in-class inhibitor, TH588 was found to be efficient in the suppression of MutT homolog1 (MTH1). A recent work shows that the inhibitory potency of TH588 against human MTH1 (hsMTH1) is approximately 20-fold over that of mouse MTH1 (mmMTH1) and identifies residue in position 116 in MTH1 has an important contribution to TH588 affinity. But the effect of residue Leu or Met in position 116 on the binding affinity remains unclear. In this study, molecular dynamics (MD) simulations and free energy calculations were used to elucidate the mechanism about the effect of residue 116 to the different inhibitory potency of TH588 against MTH1...
August 4, 2018: Journal of Molecular Graphics & Modelling
Dong Xiang, Weihua Zhu
We performed quantum molecular dynamics simulations to investigate the initiation chemistry of condensed phase δ-HMX at high temperatures by maintaining constant energy and volume to model adiabatic initiation process. The decomposition of HMX began by the C-N bond breaking in one molecule and by the C-H bond cleavage in other HMX molecule at 2400 K. At 2700 K, HMX is triggered by only one path that the C-N bond broke and the ring opened. At 3000 K, the decomposition of HMX is triggered by the C-H bond and N-O bond fission in the branch chains...
August 4, 2018: Journal of Molecular Graphics & Modelling
Serdar Durdagi, Muhammad Tahir Ul Qamar, Ramin Ekhteiari Salmas, Quratulain Tariq, Farooq Anwar, Usman Ali Ashfaq
Appropriate therapeutic solutions against Staphylococcal infections are currently limited. To work out the complex task of challenging drug resistance in Staphylococcus aureus, new compounds with novel modes of action are required. In this study, we performed target-driven virtual screening to filter exhaustive phytochemical libraries that can inhibit the activity of S. aureus DNA Gyrase B (Gyr B). Three top-ranked hit molecules (Mangostenone E, Candenatenin A and 2,4,4'-trihydroxydihydrochalcone) were identified from comprehensive molecular docking studies based on their strong spatial affinity with key catalytic residues of the binding pocket of DNA GyrB, especially with the well-known crucial residue Asp81...
July 27, 2018: Journal of Molecular Graphics & Modelling
Cuihong Wang, Yue Jiang, Meiling Zhang, Xuening Fei, Yingchun Gu
Nine novel fluorescent antifolates, 1-9, were designed and docked with FRα and FRβ. The binding energies of the bound complexes were determined by molecular docking and MM-PBSA studies. The structural properties of the complexes FR-FOL, FR-7, FR-8 and FR-9 were analyzed in detail via molecular docking and molecular dynamics studies. We further calculated the root mean square displacement and root mean square fluctuation of the bound complexes using molecular dynamics simulations. Since compounds 7, 8 and 9 are promising candidate in distinguishing FRα from FRβ, the hydrogen bond properties of complexes FRα-7, FRα-8 and FRα-9 were studied by a dispersion complemented density functional tight-binding method...
July 24, 2018: Journal of Molecular Graphics & Modelling
Subramaniam Kavitha, Palanisamy Deepa, Mylsamy Karthika, Ramasamy Kanakaraju
The electronic structure, stability, acidity, topological properties and charge transfer of octahedral magnesium-carboxylate complexes have been investigated at M05-2X/6-311G** level of theory. The interaction energy studies confirm the stability of the pentahydrated magnesium compounds. The calculated pKa values using SMD solvation model through the deprotonation of metal-ion bound water molecule vary from 15.08 to 19.36, enunciate the role of Mg-O bonds on the acidity of the Mg+2 complexes. The closed shell ionic interactions of Mg-ligand bonds are assessed by the atoms in molecules (AIM) and the electron localization function (ELF) analyses...
July 24, 2018: Journal of Molecular Graphics & Modelling
Chun-Guang Liu, Yun-Jie Chu
In the present paper, the reaction mechanism corresponding to activation of hydrogen peroxide (H2 O2 ) by a divanadium-substituted polyoxometalate (POM) [γ-PV2 W10 O38 (μ-OH)2 ]3- (I) to form catalytic active species, peroxo complex [γ-PV2 W10 O38 (μ-η2 ,η2 -O2 )]3- (III), was studied by using the density functional theory (DFT) calculations method with B3LYP functional. The results indicate that coordination of H2 O2 to I proceeds via a vanadium-center-assisted proton transfer pathway to remove the first water molecule and form a hydroperoxy intermediate [γ-PV2 W10 O38 (μ-OH) (μ-OOH)]3- (II)...
July 23, 2018: Journal of Molecular Graphics & Modelling
Carlos Gueto-Tettay, Alejandro Martinez-Consuegra, Luis Pelaez-Bedoya, Juan Carlos Drosos-Ramirez
The population density concept has emerged as a proposal for the analysis of molecular dynamics results, the key characteristic of population density is the evaluation of the simultaneous occurrence of a set of relevant parameters for a system. However, despite its statistical strength, selection of the tolerance level for the comparison of different models may appear as arbitrary. This work introduces the G-score, a function which summarizes and categorizes the results of population density analysis. Additionally, it incorporates parameters based on rmsd and dihedral angles, besides the protein-protein and protein-ligand interatomic distances conventionally used, which complement each other to provide a better description of the behavior of the system...
July 19, 2018: Journal of Molecular Graphics & Modelling
S Dharani, V Nagarajan, R Chandiramouli
The geometric stability of silicane layer (H-Si) is explored using the first-principles investigation. The electronic properties of H-Si are ascertained, and tunable electronic properties of H-Si leads to the application in sequencing the deoxyribonucleic acid (DNA)/riboxy nucleic acid (RNA). The adsorption behavior of DNA/RNA nucleobases on H-Si is explored using Bader charge transfer, adsorption energy, and energy gap. Moreover, there is a significant change in the band structure and density of states of H-Si upon adsorption of nucleobases...
July 6, 2018: Journal of Molecular Graphics & Modelling
Adebayo A Adeniyi, Jeanet Conradie
Keto-enol equilibrium is known to depend on the difference in the free energy between the keto and enol tautomers and is greatly influenced by the nature of the substituents, temperature, and the polarity of the solvents. New insight was gained into the series of twelve differently substituted β-diketones (A-L), showing that the keto form of each β-diketone has a lesser tendency towards resonance formation, compared to their enol forms. For molecules G and H (which contain an electron-withdrawing CF3 substituent), the experimentally reported high tendency towards the enol tautomer, was computationally traced to a high level of the alternative enolic resonance weight also in their keto structure, as well as to the highly favourable enolic inter-fragment stability of the energy of interaction...
June 30, 2018: Journal of Molecular Graphics & Modelling
Dirar Homouz, Kwee Hong Joyce-Tan, Mohd ShahirShamsir, Ibrahim M Moustafa, Haitham T Idriss
DNA polymerase β is a 39 kDa enzyme that is a major component of Base Excision Repair in human cells. The enzyme comprises two major domains, a 31 kDa domain responsible for the polymerase activity and an 8 kDa domain, which bind ssDNA and has a deoxyribose phosphate (dRP) lyase activity. DNA polymerase β was shown to be phosphorylated in vitro with protein kinase C (PKC) at serines 44 and 55 (S44 and S55), resulting in loss of its polymerase enzymic activity, but not its ability to bind ssDNA. In this study, we investigate the potential phosphorylation-induced structural changes for DNA polymerase β using molecular dynamics simulations...
September 2018: Journal of Molecular Graphics & Modelling
Samir S Roy, Manju Kapoor
Hsp90 contains two Nucleotide Binding Sites (NBS): one each in its N-terminal domain (NTD) and C-terminal domain (CTD), respectively. Previously we used computational techniques to locate a nucleotide-binding site in the CTD. Nucleotide binding at this site stabilized the structurally labile region within this domain, thus providing a rationale for increased resistance to thermal denaturation and proteolysis. A scan for ligand-binding sites in CTD revealed four potential sites with the requisite volume to accommodate aminocoumarins and -derived inhibitors...
September 2018: Journal of Molecular Graphics & Modelling
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