How strong is the edge effect in the adsorption of anticancer drugs on a graphene cluster?

The adsorption of nucleobase-analog anticancer drugs (fluorouracil, thioguanine, and mercaptopurine) on a graphene flake (C₅₄H₁₈) was investigated by shifting the site at which adsorption occurs from one end of the sheet to the other end. The counterpoise-corrected M06-2X/cc-pVDZ binding energies revealed that the binding stability decreases in the sequence thioguanine?>?mercaptopurine?>?fluorouracil. We found that adsorption near the middle of the sheet is more favorable than adsorption near the edge due to the edge effect. This edge effect is stronger for the adsorption of thioguanine or mercaptopurine than for fluorouracil adsorption. However, the edge effect reduces the binding energy of the drug to the flake by only a small amount, <5 kcal/mol, depending on the adsorption site and the alignment of the drug at this site.     

Theoretical studies of the role of C-terminal cysteines in the process of <Emphasis Type="Italic">S</Emphasis>-nitrosylation of human Src kinases

Src tyrosine kinases are a family of non-receptor proteins that are responsible for the growth process, cellular proliferation, differentiation and survival. Lack of Src kinase control has been associated with the development of certain human cancers. This family of proteins is constituted of four domains, with SH1 being the kinase or catalytic domain. SH1 also presents three important regulatory sites. Two residues, Tyr416 and Tyr527, are responsible for important phosphorylation processes that lead to, respectively, activation and deactivation of these kinases. More recently, however, a set of four cysteine residues located near the C-terminus-Cys483, Cys487, Cys496 and Cys498-has been associated with the activation of the Src kinases through S-nitrosylation reactions. Particularly, the Cys498 has been specified as a fundamental residue when considering this regulatory mechanism. Aiming to understand the role of these four cysteines in S-nitrosylation, theoretical studies of electrostatic, steric and hydrophobic properties were performed with a sequence of 20 amino acids, enclosing the four cysteine residues under study, extracted from the PDB coordinates of the crystal obtained from the inactive state of Src kinase. Results indicate that Cys498 is buried deeply in the protein, in hydrophobic surroundings in which NO is more likely to suffer decomposition into the electrophilic intermediates known to be responsible for S-nitrosylation reactions. Electronic calculated properties, such as punctual atomic charges, electrostatic potentials and molecular orbital energy, also demonstrated the good nucleophilic potential of Cys498.

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Graphical Abstract Structure of Src kinase with zoomed area representing the 20 amino acids comprising the CC motif extracted from the whole protein structure. Right upper panel Electrostatic potential map, right lower panel hydrophilic map in anterior view

     

Molecular dynamics simulations of a lithium/sodium carbonate mixture

The diffusion and ionic conductivity of Li _x Na_1?x CO₃ salt mixtures were studied by means of Molecular Dynamics (MD) simulations, using the Janssen and Tissen model (Janssen and Tissen, Mol Simul 5:83–98; 1990). These salts have received particular attention due to their central role in fuel cells technology, and reliable numerical methods that could perform as important interpretative tool of experimental data are thus required but still lacking. The chosen computational model nicely reproduces the main structural behaviour of the pure Li₂CO₃, Na₂CO₃ and K₂CO₃ carbonates, but also of their Li/K and Li/Na mixtures. However, it fails to accurately describe dynamic properties such as activation energies of diffusion and conduction processes, outlining the need to develop more accurate models for the simulation of molten salt carbonates.     

DFT investigation on the decarboxylation mechanism of <Emphasis Type="Italic">ortho</Emphasis> hydroxy benzoic acids with acid catalysis

A density functional theory (DFT) study was performed to explore the mechanisms of the acid-catalyzed decarboxylation reaction of salicylic acids using the B3LYP method with 6-31++G(d,p) basis set in both gas phase and aqueous environment. The α-protonated cation of carboxylate acid was formed during the decarboxylation process in acidic conditions, and the presence of hydrogen ions promotes decarboxylation greatly by significantly decreasing the overall reaction energy barriers to 20.98 kcal mol^?1 in gas phase and 20.93 kcal mol^?1 in water, respectively. The hydrogen in the α-carbon came directly from the acid rather than from the carboxyl group in neutral state. Compared with the reaction in gas phase, water in aqueous state causes the reaction to occur more easily. Substituents of methyl group, chlorine and fluorine at the ortho-position to the carboxyl of salicylic acid could further lower the decarboxylation energy barriers and facilitate the reaction.     

Effects of landscape and management on ground‐dwelling insect assemblages of farmland in Jeju Island,Korea

Granite‐derived soils are widespread in the farmland of Korea in general. In contrast, Jeju Island has mainly volcanic ash soils. Soils and weather condition in Jeju Island created a unique agricultural system. We identified the features of ground‐dwelling insects in farmlands of Jeju Island. This study was conducted in four areas (Samdal‐ri and Susan‐ri in Seogwipo city, and Dongmyeong‐ri and Suwon‐ri in Jeju city) in Jeju Island, Korea. Field surveys were carried out twice in summer (June) and autumn (September) in 2013. Ground‐dwelling insects were sampled quantitatively by using pitfall traps. As a result, in total 3322 individuals, 137 species, 48 families and 8 orders were investigated in farmlands of Jeju Island. Especially, members of Coleoptera and Hymenoptera accounted for a large proportion of ground‐dwelling insect communities. The numbers of species and individuals for major taxonomic groups showed significant regional and seasonal differences. This study implied that the seasonal and regional differences of ground‐dwelling insect communities were affected by surrounding land use patterns, life history patterns of each taxonomic group and farmland management.     

First finding of a quarantine pest,Atherigona (Acritochaeta) orientalis Schiner (Diptera: Muscidae), in Korea

The invasive quarantine pest fly, Atherigona (Acritochaeta) orientalis Schiner, is observed for the first time in tomato greenhouses in Gyeongsangbuk‐do, Korea. The genus Atherigona Rondani is also newly added to Korean fauna. Allium tuberosum is listed as a new host crop for this species. Some morphological characteristics for accurate identification and host lists are given to provide plant quarantine information for pest management.     

Generalized logical model based on network topology to capture the dynamical trends of cellular signaling pathways

Background

Cellular responses to extracellular perturbations require signaling pathways to capture and transmit the signals. However, the underlying molecular mechanisms of signal transduction are not yet fully understood, thus detailed and comprehensive models may not be available for all the signaling pathways. In particular, insufficient knowledge of parameters, which is a long-standing hindrance for quantitative kinetic modeling necessitates the use of parameter-free methods for modeling and simulation to capture dynamic properties of signaling pathways.

Results

We present a computational model that is able to simulate the graded responses to degradations, the sigmoidal biological relationships between signaling molecules and the effects of scheduled perturbations to the cells. The simulation results are validated using experimental data of protein phosphorylation, demonstrating that the proposed model is capable of capturing the main trend of protein activities during the process of signal transduction. Compared with existing simulators, our model has better performance on predicting the state transitions of signaling networks.

Conclusion

The proposed simulation tool provides a valuable resource for modeling cellular signaling pathways using a knowledge-based method.

     

Prediction of drugs having opposite effects on disease genes in a directed network

Background

Developing novel uses of approved drugs, called drug repositioning, can reduce costs and times in traditional drug development. Network-based approaches have presented promising results in this field. However, even though various types of interactions such as activation or inhibition exist in drug-target interactions and molecular pathways, most of previous network-based studies disregarded this information.

Methods

We developed a novel computational method, Prediction of Drugs having Opposite effects on Disease genes (PDOD), for identifying drugs having opposite effects on altered states of disease genes. PDOD utilized drug-drug target interactions with ‘effect type’, an integrated directed molecular network with ‘effect type’ and ‘effect direction’, and disease genes with regulated states in disease patients. With this information, we proposed a scoring function to discover drugs likely to restore altered states of disease genes using the path from a drug to a disease through the drug-drug target interactions, shortest paths from drug targets to disease genes in molecular pathways, and disease gene-disease associations.

Results

We collected drug-drug target interactions, molecular pathways, and disease genes with their regulated states in the diseases. PDOD is applied to 898 drugs with known drug-drug target interactions and nine diseases. We compared performance of PDOD for predicting known therapeutic drug-disease associations with the previous methods. PDOD outperformed other previous approaches which do not exploit directional information in molecular network. In addition, we provide a simple web service that researchers can submit genes of interest with their altered states and will obtain drugs seeming to have opposite effects on altered states of input genes at http://gto.kaist.ac.kr/pdod/index.php/main.

Conclusions

Our results showed that ‘effect type’ and ‘effect direction’ information in the network based approaches can be utilized to identify drugs having opposite effects on diseases. Our study can offer a novel insight into the field of network-based drug repositioning.

     

FK506 positively regulates the migratory potential of melanocyte‐derived cells by enhancing syndecan‐2 expression

Although topical tacrolimus (FK506) is known to promote repigmentation by increasing the pigmentation and migration of melanocytes, the mechanism through which FK506 regulates cell migration remains unclear. Here, we report that FK506 treatment enhanced cell spreading on laminin‐332 and increased migration in both melanocytes and melanoma cells. Interestingly, FK506 also increased the expression of syndecan‐2, a transmembrane heparan sulfate proteoglycan through c‐jun terminal kinase activation. Moreover, siRNA‐mediated reduction of syndecan‐2 expression decreased FK506‐mediated cell spreading and migration in melanoma cells and decreased focal adhesion kinase phosphorylation in both melanocytes and melanoma cells. Consistent with these effects on syndecan‐2 expression, FK506 enhanced the membrane and melanosome localizations of PKCβII, a regulator of tyrosinase activity. This suggests that FK506 may play a dual regulatory role by affecting both melanogenesis and migration in melanocyte‐derived cells. Interestingly, however, FK506 failed to show any synergistic effect on the migration of UVB‐treated melanocyte‐derived cells. Taken together, these data indicate that FK506 regulates cell migration by enhancing syndecan‐2 expression, further suggesting that syndecan‐2 could be a potential target for the treatment of patients with vitiligo.