Solution structure of a designed cyclic peptide ligand for nickel and copper ions

Nuclear magnetic resonance (NMR) spectroscopy was used to study a cyclic peptide derived from the amino-terminal copper-and-nickel-binding (ATCUN) motif. The three-dimensional structure of the unliganded peptide in aqueous solution was solved by simulated annealing using distance constraints derived from Nuclear Overhauser Effects. A structural model for the Ni(II)-bound complex was also produced based on NMR evidence and prior spectroscopic data, which are consistent with crystal structures of linear ATCUN complexes. Structural interpolation, or ‘morphing’, was used to understand the transition of this highly structured cyclic peptide from its unliganded structure to its metal-ion-bound structure.     

Synthesis of a novel methylene-bridged biscarbazole derivative and evaluation of its DNA and nucleotide binding properties

The synthesis of a novel methylene-bridged biscarbazole derivative 1 was described and the possible mechanism for its unexpectedly synthesized intermediate, compound A, was postulated. The binding properties of 1 to both Ct-DNA and nucleotides were investigated via fluorescent and UV–Vis spectra. The spectral investigations illustrated that this binary carbazole exhibited higher binding abilities to both Ct-DNA and nucleotides than its monomeric form, owing to the structurally flexible nature of double carbazole moieties fine-tuned by this non rigid methylene-linkage.     

Coarse‐grained molecular dynamics simulations of protein–ligand binding

Coarse‐grained molecular dynamics (CGMD) simulations with the MARTINI force field were performed to reproduce the protein–ligand binding processes. We chose two protein–ligand systems, the levansucrase–sugar (glucose or sucrose), and LinB–1,2‐dichloroethane systems, as target systems that differ in terms of the size and shape of the ligand‐binding pocket and the physicochemical properties of the pocket and the ligand. Spatial distributions of the Coarse‐grained (CG) ligand molecules revealed potential ligand‐binding sites on the protein surfaces other than the real ligand‐binding sites. The ligands bound most strongly to the real ligand‐binding sites. The binding and unbinding rate constants obtained from the CGMD simulation of the levansucrase–sucrose system were approximately 10 times greater than the experimental values; this is mainly due to faster diffusion of the CG ligand in the CG water model. We could obtain dissociation constants close to the experimental values for both systems. Analysis of the ligand fluxes demonstrated that the CG ligand molecules entered the ligand‐binding pockets through specific pathways. The ligands tended to move through grooves on the protein surface. Thus, the CGMD simulations produced reasonable results for the two different systems overall and are useful for studying the protein–ligand binding processes. © 2014 Wiley Periodicals, Inc.     

Performance of density‐functional tight‐binding models in describing hydrogen‐bonded anionic‐water clusters

Density‐functional tight‐binding (DFTB) models are computationally efficient approximations to density‐functional theory that have been shown to predict reliable structural and energetic properties for various systems. In this work, the reliability and accuracy of the self‐consistent‐charge DFTB model and its recent extension(s) in predicting the structures, binding energies, charge distributions, and vibrational frequencies of small water clusters containing polyatomic anions of the Hofmeister series (carbonate, sulfate, hydrogen phosphate, acetate, nitrate, perchlorate, and thiocyanate) have been carefully and systematically evaluated on the basis of high‐level ab initio quantum‐chemistry [MP2/aug‐cc‐pVTZ and CCSD(T)/aug‐cc‐pVQZ] reference data. Comparison with available experimental data has also been made for further validation. The self‐consistent‐charge DFTB model, and even more so its recent extensions, are shown to properly account for the structural properties, energetics, intermolecular polarization, and spectral signature of hydrogen‐bonding in anionic water clusters at a fraction of the computational cost of ab initio quantum‐chemistry methods. This makes DFTB models candidates of choice for investigating much larger systems such as seeded water droplets, their structural properties, formation thermodynamics, and infrared spectra. © 2014 Wiley Periodicals, Inc.     

An Untargeted Metabolomics Approach for Correlating Pulse Crop Seed Coat Polyphenol Profiles with Antioxidant Capacity and Iron Chelation Ability

Pulse crop seed coats are a sustainable source of antioxidant polyphenols, but are typically treated as low-value products, partly because some polyphenols reduce iron bioavailability in humans. This study correlates antioxidant/iron chelation capabilities of diverse seed coat types from five major pulse crops (common bean, lentil, pea, chickpea and faba bean) with polyphenol composition using mass spectrometry. Untargeted metabolomics was used to identify key differences and a hierarchical analysis revealed that common beans had the most diverse polyphenol profiles among these pulse crops. The highest antioxidant capacities were found in seed coats of black bean and all tannin lentils, followed by maple pea, however, tannin lentils showed much lower iron chelation among these seed coats. Thus, tannin lentils are more desirable sources as natural antioxidants in food applications, whereas black bean and maple pea are more suitable sources for industrial applications. Regardless of pulse crop, proanthocyanidins were primary contributors to antioxidant capacity, and to a lesser extent, anthocyanins and flavan-3-ols, whereas glycosylated flavonols contributed minimally. Higher iron chelation was primarily attributed to proanthocyanidin composition, and also myricetin 3-O-glucoside in black bean. Seed coats having proanthocyanidins that are primarily prodelphinidins show higher iron chelation compared with those containing procyanidins and/or propelargonidins.     

How Does Glycation Affect Binding Parameters of the Albumin-Gliclazide System in the Presence of Drugs Commonly Used in Diabetes? In Vitro Spectroscopic Study

In this research, the selected drugs commonly used in diabetes and its comorbidities (gliclazide, cilazapril, atorvastatin, and acetylsalicylic acid) were studied for their interactions with bovine serum albumin—native and glycated. Two different spectroscopic methods, fluorescence quenching and circular dichroism, were utilized to elucidate the binding interactions of the investigational drugs. The glycation process was induced in BSA by glucose and was confirmed by the presence of advanced glycosylation end products (AGEs). The interaction between albumin and gliclazide, with the presence of another drug, was confirmed by calculation of association constants (0.11–1.07 × 10⁴ M⁻¹). The nature of changes in the secondary structure of a protein depends on the drug used and the degree of glycation. Therefore, these interactions may have an influence on pharmacokinetic parameters.     

Discovery of Novel Diarylamide N-Containing Heterocyclic Derivatives as New Tubulin Polymerization Inhibitors with Anti-Cancer Activity

Tubulin has been regarded as an attractive and successful molecular target in cancer therapy and drug discovery. Vicinal diaryl is a simple scaffold found in many colchicine site tubulin inhibitors, which is also an important pharmacophoric point of tubulin binding and anti-cancer activity. As the continuation of our research work on colchicine binding site tubulin inhibitors, we designed and synthesized a series of diarylamide N-containing heterocyclic derivatives by the combination of vicinal diaryl core and N-containing heterocyclic skeletons into one hybrid though proper linkers. Among of these compounds, compound 15b containing a 5-methoxyindole group exhibited the most potent inhibitory activity against the tested three human cancer cell lines (MGC-803, PC-3 and EC-109) with IC₅₀ values of 1.56 μM, 3.56 μM and 14.5 μM, respectively. Besides, the SARs of these compounds were preliminarily studied and summarized. The most active compound 15b produced the inhibition of tubulin polymerization in a dose-dependent manner and caused microtubule network disruption in MGC-803 cells. Therefore, compound 15b was identified as a novel tubulin polymerization inhibitor targeting the colchicine binding site. In addition, the results of molecular docking also suggested compound 15b could tightly bind into the colchicine binding site of β-tubulin.     

Stereodivergent Anion Binding Catalysis with Molecular Motors

A photoresponsive chiral catalyst based on an oligotriazole‐functionalized unidirectional molecular motor has been developed for stereodivergent anion binding catalysis. The motor function controls the helical chirality of supramolecular assemblies with chloride anions, which by means of chirality transfer enables the enantioselective addition of a silyl ketene acetal nucleophile to oxocarbenium cations. Reversal of stereoselectivity (up to 142 % Δee) was achieved through rotation of the motor core induced by photochemical and thermal isomerization steps.     

How Ligand Binding Affects the Dynamical Transition Temperature in Proteins

The biochemical functions of proteins are activated at the protein glass transition temperature, which has been proposed to be dependent upon protein-water interactions. However, at the molecular level it is unclear how ligand binding to well-defined binding sites can influence this transition temperature. We thus report molecular dynamics (MD) simulations of the ϵ subunit from thermophilic Bacillus PS3 in the ATP-free and ligand-bound states over a range of temperatures from 20 to 300 K, to study the influence of ligand association upon the transition temperature. We also measure the protein mean square displacement (MSD) in each state, which is well established as a means to quantify this dynamical temperature dependence. We find that the transition temperature is largely unaffected by ligand association, but the MSD beyond the transition temperature increases more rapidly in the ATP-free state. Our data suggests that ligands can effectively “shield” a binding site from solvent, and hence stabilize protein domains with increasing temperature.