A theoretical study of a series of five glucose based glycolipid crown ethers and their complexes with Na(+) and K(+) was performed using the density functional theory with B3LYP/6-31 G* to obtain the optimized geometrical structures and electronic properties. The local nucleophilicity of the five molecules was investigated using Fukui function, while the global nucleophilicity was calculated from the ionization potential and electron affinity. The structures and coordination of the complexes were studied to identify the best match of the glycolipid crown ethers with cations. In general, it was found that the oxygen atoms pairs O2 and O3 (or O4 and O6) on the sugar ring are constrained from moving toward the cation, which results in a weaker O-cation coordination strength for the oxygen pair compared to the other oxygen atoms in the crown ether ring. The thermodynamic properties of the binding of the complexes and the exchange reaction in gas phase were evaluated. The cation selectivity pattern among the five molecules was in good agreement with the experiment.
Density functional theory calculations on two glycosides, namely, n-octyl-β-D-glucopyranoside (C(8)O-β-Glc) and n-octyl-β-D-galactopyranoside (C(8)O-β-Gal) were performed for geometry optimization at the B3LYP/6-31G level. Both molecules are stereoisomers (epimers) differing only in the orientation of the hydroxyl group at the C4 position. Thus it is interesting to investigate electronically the effect of the direction (axial/equatorial) of the hydroxyl group at the C4 position. The structure parameters of X-H∙∙∙Y intramolecular hydrogen bonds were analyzed, while the nature of these bonds and the intramolecular interactions were considered using the atoms in molecules (AIM) approach. Natural bond orbital analysis (NBO) was used to determine bond orders, charge and lone pair electrons on each atom and effective non-bonding interactions. We have also reported electronic energy and dipole moment in gas and solution phases. Further, the electronic properties such as the highest occupied molecular orbital, lowest unoccupied molecular orbital, ionization energy, electron affinity, electronic chemical potential, chemical hardness, softness and electrophilicity index, are also presented here for both C(8)O-β-Glc and C(8)O-β-Gal. These results show that, while C(8)O-β-Glc possess- only one hydrogen bond, C(8)O-β-Gal has two intramolecular hydrogen bonds, which further confirms the anomalous stability of the latter in self-assembly phenomena.
5-HT(1A) serotonin and D1 dopamine receptor agonists have been postulated to be able to improve negative and cognitive impairment symptoms of schizophrenia, while partial agonists and antagonists of the D2 and 5-HT(2A) receptors have been reported to be effective in reducing positive symptoms. There is therefore a need for well-defined homology models for the design of more selective antipsychotic agents, since no three-dimensional (3D) crystal structures of these receptors are currently available. In this study, homology models were built based on the high-resolution crystal structure of the β(2)-adrenergic receptor (2RH1) and further refined via molecular dynamics simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer system with the GROMOS96 53A6 united atom force field. Docking evaluations with representative agonists and antagonists using AutoDock 4.2 revealed binding modes in agreement with experimentally determined site-directed mutagenesis data and significant correlations between the computed and experimental pK (i) values. The models are also able to distinguish between antipsychotic agents with different selectivities and binding affinities for the four receptors, as well as to differentiate active compounds from decoys. Hence, these human 5-HT(1A), 5-HT(2A), D1 and D2 receptor homology models are capable of predicting the activities of novel ligands, and can be used as 3D templates for antipsychotic drug design and discovery.
The effect of organic solvent on the structure and dynamics of proteins was investigated by multiple molecular dynamics simulations (1 ns each) of Candida rugosa lipase in water and in carbon tetrachloride. The choice of solvent had only a minor structural effect. For both solvents the open and the closed conformation of the lipase were near to their experimental X-ray structures (C(alpha) rms deviation 1-1.3 A). However, the solvents had a highly specific effect on the flexibility of solvent-exposed side chains: polar side chains were more flexible in water, but less flexible in organic solvent. In contrast, hydrophobic residues were more flexible in organic solvent, but less flexible in water. As a major effect solvent changed the dynamics of the lid, a mobile element involved in activation of the lipase, which fluctuated as a rigid body about its average position. While in water the deviations were about 1.6 A, organic solvent reduced flexibility to 0.9 A. This increase rigidity was caused by two salt bridges (Lys85-Asp284, Lys75-Asp79) and a stable hydrogen bond (Lys75-Asn 292) in organic solvent. Thus, organic solvents stabilize the lid but render the side chains in the hydrophobic substrate-binding site more mobile. [figure: see text]. Superimposition of open (black, PDB entry 1CRL) and closed (gray, PDB entry 1TRH) conformers of C. rugosa lipase. The mobile lid is indicated.
Today, drug delivery systems based on nanostructures have become the most efficient to be studied. Recent studies revealed that the fullerenes can be used as drug carriers and transport drugs in a target cell. The aim of the present work is to study the interaction of C60 fullerene containing porphyrin-like transition metal-N4 clusters (TMN4C55, TM = Fe, Co, and Ni) with a non-steroidal anti-inflammatory drug (ibuprofen (Ibp)) by employing the method of the density functional theory. Results showed that the C60 fullerene with TMN4 clusters could significantly enhance the tendency of C60 for adsorption of ibuprofen drug. Also, our ultraviolet-visible results show that the electronic spectra of Ibp/TMN4C55 complexes exhibit a blue shift toward lower wavelengths (higher energies). It was found that the NiN4C55 fullerene had high chemical reactivity, which was important for binding of the drug onto the carrier surface. In order to gain insight into the binding features of Ibp/TMN4C55 complexes, the atoms in molecules analysis was also performed. Our results exhibit the electrostatic features of the Ibp/TMN4C55 bonding. Consequently, this study demonstrated that the TMN4C55 fullerenes could be used as potential carriers for delivery of Ibp drug in the nanomedicine domain. Graphical Abstract The TMN4C55 (TM=Fe, Co, and Ni) fullerenes could be used as potential carriers for delivery of ibuprofen drug in the nanomedicine domain.
Recent outbreaks of highly pathogenic influenza strains have highlighted the need to develop new anti-influenza drugs. Here, we report an in silico study of carvone derivatives to analyze their binding modes with neuraminidase (NA) active sites. Two proposed carvone analogues, CV(A) and CV(B), with 36 designed ligands were predicted to inhibit NA (PDB ID: 3TI6) using molecular docking. The design is based on structural resemblance with the commercial inhibitor, oseltamivir (OTV), ligand polarity, and amino acid residues in the NA active sites. Docking simulations revealed that ligand A18 has the lowest energy binding (∆Gbind) value of -8.30 kcal mol-1, comparable to OTV with ∆Gbind of -8.72 kcal mol-1. A18 formed seven hydrogen bonds (H-bonds) at residues Arg292, Arg371, Asp151, Trp178, Glu227, and Tyr406, while eight H-bonds were formed by OTV with amino acids Arg118, Arg292, Arg371, Glu119, Asp151, and Arg152. Molecular dynamics (MD) simulation was conducted to compare the stability between ligand A18 and OTV with NA. Our simulation study showed that the A18-NA complex is as stable as the OTV-NA complex during the MD simulation of 50 ns through the analysis of RMSD, RMSF, total energy, hydrogen bonding, and MM/PBSA free energy calculations.
The arginine repressor (ArgR) of Escherichia coli binds to six L-arginine molecules that act as its co-repressor in order to bind to DNA. The binding of L-arginine molecules as well as its structural analogues is compared by means of computational docking. A grid-based energy evaluation method combined with a Monte Carlo simulated annealing process was used in the automated docking. For all ligands, the docking procedure proposed more than one binding site in the C-terminal domain of ArgR (ArgRc). Interaction patterns of ArgRc with L-arginine were also observed for L-canavanine and L-citrulline. L-lysine and L-homoarginine, on the other hand, were shown to bind poorly at the binding site. Figure A general overview of the sites found from docking the various ligands into ArgRc ( grey ribbons). Red coloured sticks: residues in binding site H that was selected for docking
In the present study, we use the state of art density functional theory (DFT) techniques to calculate the structural, optoelectronic and nonlinear optical (NLO) properties for two novel chalcone derivatives. The geometrical structures of chalcone derivatives compound 1 and 2 are optimized using periodic boundary conditions (PBC) in solid-state phase as well as isolated single molecular geometry in the gas phase. The reasonable agreement is found among experimental, solid-state and gas phase single molecular geometries, which provide us, further confidence to explore the potential of above-entitled derivatives as good functional materials for electro-optical applications. For instance, the frequency dependent real parts of dielectric functions are calculated for compound 1 and 2. The maximum value of real part of the dielectric function for compound 1 and 2 at 0eV are computed as 4.35 and 6.68 for the polarization vectors of (001) directions, respectively, which reveals the fact that the compound 1 and 2 might be good charge transport materials. The reflectivities of the compound 1 and 2 are 0.64 and 0.45 revealing that the compound 2 might be more efficient material for organic photovoltaic (OPV) applications. The results of the refractive index improved by doping the strong electron withdrawing groups (EWGs) shows that the compound 2 might be good refractor of the photon as compared to compound 1. The calculated values for static second-order polarizability are 3498 and 10464 a. u. and for frequency dependent second harmonic generations are 2557 and 6429 a. u. for compound 1 and 2, respectively, which indicates their significant potential for possible nonlinear optical applications.
De novo approach was applied to design single chain fragment variable (scFv) for BmR1, a recombinant antigen from Bm17DIII gene which is the primary antigen used for the detection of anti-BmR1 IgG4 antibodies in the diagnostic of lymphatic filariasis. Three epitopes of the BmR1 was previously predicted form an ab initio derived three-dimensional structure. A collection of energetically favourable conformations was generated via hot-spot-centric approach. This resulted in a set of three different scFv scaffolds used to compute the high shape complementary conformations via dock-and-design approach with the predicted epitopes of BmR1. A total of 4227 scFv designs were generated where 200 scFv designs produced binding energies of less than -20 R.E.U with shape complementarity higher than 0.5. We further selected the design with at least one hydrogen bond and one salt bridge with the epitope, thus resulted in a total of 10, 1 and 19 sFv designs for epitope 1, 2 and 3, respectively. The results thus showed that de novo design can be an alternative approach to yield high affinity in silico scFv designs as a starting point for antibody or specific binder discovery processes.
Structural parameters, electronic structure and optical properties of the dialkali metal monotelluride M2Te (M = Li, Na, K and Rb) compounds in the cubic antifluorite structure were investigated via ab initio calculations using the all electron linearized augmented plane wave approach based on density functional theory with and without including spin-orbit coupling (SOC). The exchange-correlation interactions were described within the PBEsol version of the generalized gradient approximation and Tran-Blaha modified Becke-Johnson potential (TB-mBJ). Optimized equilibrium lattice parameters are in excellent accordance with existing measured ones. Computed energy band dispersions show that the studied compounds are large band gap materials. Inclusion of SOC reduces the band gap value compared to the corresponding one calculated without including SOC. Determination of the energy band character and interatomic bonding nature are performed using the densities of states diagrams and charge density distribution map. Linear optical function spectra are predicted for a wide energy range and the origin of the dielectric function spectrum peaks are determined.
Protein-ligand binding free energy values of wild-type and mutant C-terminal domain of Escherichia coli arginine repressor (ArgRc) protein systems bound to L-arginine or L-citrulline molecules were calculated using the linear interaction energy (LIE) method by molecular dynamics (MD) simulation. The binding behaviour predicted by the dissociation constant (K(d)) calculations from the binding free energy values showed preferences for binding of L-arginine to the wild-type ArgRc but not to the mutant ArgRc(D128N). On the other hand, L-citrulline do not favour binding to wild-type ArgRc but prefer binding to mutant ArgRc(D128N). The dissociation constant for the wild-type ArgRc-L-arginine complex obtained in this study is in agreement with reported experimental results. Our results also support the experimental data for the binding of L-citrulline to the mutant ArgRc(D128N). These showed that LIE method for protein-ligand binding free energy calculation could be applied to the wild-type and the mutant E. coli ArgRc-L-arginine and ArgRc-L-citrulline protein-ligand complexes and possibly to other transcriptional repressor-co-repressor systems as well.
Carbon nanotubes (CNTs) have received enormous attention due to their fascinating properties to be used in various applications including electronics, sensing, energy storage and conversion. The first principles calculations within density functional theory (DFT) have been carried out in order to investigate the structural, electronic and optical properties of un-doped and doped CNT nanostructures. O2, CO2, and CH3OH have been chosen as gas molecules to study the adsorption properties based on zigzag (8,0) SWCNTs. The results demonstrate that the adsorption of O2, CO2, and CH3OH gas molecules on pristine, Si-doped and B-doped SWCNTs are either physisorption or chemisorption. Moreover, the electronic properties indicating SWCNT shows significant improvement toward gas adsorption which provides the impact of selecting the best gas sensor materials towards detecting gas molecule. Therefore, these pristine, Si-, and B-doped SWCNTs can be considered to be very good potential candidates for sensing application.
The pathogenic dengue virus (DV) is a growing global threat, particularly in South East Asia, for which there is no specific treatment available. The virus possesses a two-component (NS2B/NS3) serine protease that cleaves the viral precursor proteins. Here, we performed molecular dynamics simulations of the NS2B/NS3 protease complexes with six peptide substrates (capsid, intNS3, 2A/2B, 4B/5, 3/4A and 2B/3 containing the proteolytic site between P(1) and P(1)' subsites) of DV type 2 to compare the specificity of the protein-substrate binding recognition. Although all substrates were in the active conformation for cleavage reaction by NS2B/NS3 protease, their binding strength was somewhat different. The simulated results of intermolecular hydrogen bonds and decomposition energies suggested that among the ten substrate residues (P(5)-P(5)') the P(1) and P(2) subsites play a major role in the binding with the focused protease. The arginine residue at these two subsites was found to be specific preferential binding at the active site with a stabilization energy of intNS3>2A/2B>4B/5>3/4A>2B/3 in a relative correspondence with previous experimentally derived values.
Cutinase belongs to a group of enzymes that catalyze the hydrolysis of esters and triglycerides. Structural studies on the enzyme from Fusarium solani have revealed the presence of a classic catalytic triad that has been implicated in the enzyme's mechanism. We have solved the crystal structure of Glomerella cingulata cutinase in the absence and in the presence of the inhibitors E600 (diethyl p-nitrophenyl phosphate) and PETFP (3-phenethylthio-1,1,1-trifluoropropan-2-one) to resolutions between 2.6 and 1.9 A. Analysis of these structures reveals that the catalytic triad (Ser136, Asp191, and His204) adopts an unusual configuration with the putative essential histidine His204 swung out of the active site into a position where it is unable to participate in catalysis, with the imidazole ring 11 A away from its expected position. Solution-state NMR experiments are consistent with the disrupted configuration of the triad observed crystallographically. H204N, a site-directed mutant, was shown to be catalytically inactive, confirming the importance of this residue in the enzyme mechanism. These findings suggest that, during its catalytic cycle, cutinase undergoes a significant conformational rearrangement converting the loop bearing the histidine from an inactive conformation, in which the histidine of the triad is solvent exposed, to an active conformation, in which the triad assumes a classic configuration.
A thermophilic Bacillus stearothermophilus F1 produces an extremely thermostable serine protease. The F1 protease sequence was used to predict its three-dimensional (3D) structure to provide better insights into the relationship between the protein structure and biological function and to identify opportunities for protein engineering. The final model was evaluated to ensure its accuracy using three independent methods: Procheck, Verify3D, and Errat. The predicted 3D structure of F1 protease was compared with the crystal structure of serine proteases from mesophilic bacteria and archaea, and led to the identification of features that were related to protein stabilization. Higher thermostability correlated with an increased number of residues that were involved in ion pairs or networks of ion pairs. Therefore, the mutants W200R and D58S were designed using site-directed mutagenesis to investigate F1 protease stability. The effects of addition and disruption of ion pair networks on the activity and various stabilities of mutant F1 proteases were compared with those of the wild-type F1 protease.
The binding selectivity of the M(phen)(edda) (M=Cu, Co, Ni, Zn; phen=1,10-phenanthroline, edda=ethylenediaminediacetic acid) complexes towards ds(CG)(6), ds(AT)(6) and ds(CGCGAATTCGCG) B-form oligonucleotide duplexes were studied by CD spectroscopy and molecular modeling. The binding mode is intercalation and there is selectivity towards AT-sequence and stacking preference for A/A parallel or diagonal adjacent base steps in their intercalation. The nucleolytic properties of these complexes were investigated and the factors affecting the extent of cleavage were determined to be: concentration of complex, the nature of metal(II) ion, type of buffer, pH of buffer, incubation time, incubation temperature, and the presence of hydrogen peroxide or ascorbic acid as exogenous reagents. The fluorescence property of these complexes and its origin were also investigated. The crystal structure of the Zn(phen)(edda) complex is reported in which the zinc atom displays a distorted trans-N(4)O(2) octahedral geometry; the crystal packing features double layers of complex molecules held together by extensive hydrogen bonding that inter-digitate with adjacent double layers via pi...pi interactions between 1,10-phenanthroline residues. The structure is compared with that of the recently described copper(II) analogue and, with the latter, included in molecular modeling.
The Ph3PAu[SC(OR)=NPh], R=Me (1), Et (2) and iPr (3), compounds are significantly cytotoxic to the HT-29 cancer cell line with 1 being the most active. Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis is demonstrated and both the extrinsic and intrinsic pathways of apoptosis have been shown to occur. Compound 1 activates the p73 gene, whereas each of 2 and 3 activates the p53 gene. An additional apoptotic mechanism is exhibited by 2, that is, via the JNK/MAP pathway.
Several histone deacetylase inhibitors (HDACis) are known to increase Survival Motor Neuron 2 (SMN2) expression for the therapy of spinal muscular atrophy (SMA). We aimed to compare the effects of suberoylanilide hydroxamic acid (SAHA) and Dacinostat, a novel HDACi, on SMN2 expression and to elucidate their acetylation effects on the methylation of the SMN2. Cell-based assays using type I and type II SMA fibroblasts examined changes in transcript expressions, methylation levels and protein expressions. In silico methods analyzed the intermolecular interactions between each compound and HDAC2/HDAC7. SMN2 mRNA transcript levels and SMN protein levels showed notable increases in both cell types, except for Dacinostat exposure on type II cells. However, combined compound exposures showed less pronounced increase in SMN2 transcript and SMN protein level. Acetylation effects of SAHA and Dacinostat promoted demethylation of the SMN2 promoter. The in silico analyses revealed identical binding sites for both compounds in HDACs, which could explain the limited effects of the combined exposure. With the exception on the effect of Dacinostat in Type II cells, we have shown that SAHA and Dacinostat increased SMN2 transcript and protein levels and promoted demethylation of the SMN2 gene.
A study was carried out to investigate the effects of Centella asiatica leaf on lipid metabolism of oxidative stress rats. The rats were fed 0.1% hydrogen peroxide (H(2)O(2)) with either 0.3% (w/w) C. asiatica extract, 5%C. asiatica powder (w/w), or 0.3% (w/w) alpha-tocopherol for 25 wk. Results of the study showed that C. asiatica powder significantly (P < 0.05) lowered serum low-density lipoprotein compared to that of control rats (rats fed H(2)O(2) only). At the end of the study C. asiatica-fed rats were also found to have significantly (P < 0.05) higher high-density lipoprotein and lower triglyceride level compared to rats fed only normal diet. However, cholesterol level of rats fed both C. asiatica extract and powder was found to be significantly (P < 0.05) higher compared to that of control rats. It was interesting to note that consumption of C. asiatica significantly decreased body and liver weights of the rats. Histological examinations revealed no obvious changes in all rats studied. Quantitative analysis of C. asiatica leaf revealed high concentration of total phenolic compounds, in particular, catechin, quercetin, and rutin.
The effect of room temperature ionic liquid (RTIL) on the formation of the fluorescence ternary complex oxalate-sodium morin-5-sulfonate (NaMSA)-Aluminium(III) has been studied. In weakly acidic medium and in the presence of RTIL, 1-Butyl-3-methylimidazolium hexafluorophosphate (BMIM-PF6), total complex formation is achieved as compared with the formation of the binary complex of NaMSA-Aluminium(III). The fluorescence characteristics of the system allowed the establishment of a very sensitive method for the spectrofluorimetric determination of oxalate ion. The ternary complex formed its highest fluorescence signal at 513 nm and excitation at 420 nm. In these conditions, the method produces a detection limit of 0.57 ng mL(-1). The procedure has been satisfactorily applied to the determination of oxalate ion in a vegetal tissue (spinach leaves).