Preventing the amyloid-beta peptides accumulation on the cell membrane by applying GHz electric fields: A molecular dynamic simulation.

Alzheimer's disease is associated with accumulating different amyloid peptides on the nerve cell membranes. The non-thermal effects of the GHz electric fields in this topic have yet to be well recognized. Hence, in this study, the impacts of 1 and 5 GHz electric fields on the amyloid peptide proteins accumulation on the cell membrane have been investigated, utilizing molecular dynamics (MD) simulation. The obtained results indicated that this range of electric fields did not significantly affect the peptide structure. Moreover, it was found that the peptide penetration into the membrane was increased as the field frequency was increased when the system was exposed to a 20 mv/nm oscillating electric field. In addition, it was observed that the protein-membrane interaction is reduced significantly in the presence of the 70 mv/nm electric field. The molecular level results reported in this study could be helpful in better understanding Alzheimer's disease.

Comparative chemical examination of inclusion complexes formed with ß-cyclodextrin derivatives and basic amino acids.

In this study, we have investigated the host-guest inclusion complexes between ß-cyclodextrin (ßCD), 2-hydroxypropyl-ß-cyclodextrin (2-HPßCD), and mono-6-tosyl-ß-cyclodextrin (TS-ßCD) excipients and two amino acids, such as L-arginine (L-Arg) and L-lysine (L-Lys). The formation of inclusion complexes was detected, and a comparative study was conducted at different pH, density, and viscosity. A physical mixture, comprising equal amount of amino acids was used to prepare the complex in a solid-state form. The experimental parameters, such as apparent molar volume, limiting apparent molar volume, partial molar volume were analyzed by measuring density at infinite dilution. The other quantities, such as dynamic viscosity, kinematic viscosity, relative viscosity, intrinsic viscosity, spatial viscosity, activation energy were determined for amino acid/ßCD complexes at various mass fractions of ßCDs and different temperatures. Finally, we found moderate (R2 > 0.5) and strong (R2 > 0.7) linear relationships (p-value < 0.0001) between the dynamic viscosity and the temperature: the temperature evaluation promotes the decrease in dynamic viscosity for amnio acid-ßCD (its derivatives) complexes. The results of this study emphasize important properties of analyzed complexes that can be utilized in the development of controlled drug delivery vectors.

Probing inclusion complexes of 2-hydroxypropyl-ß-cyclodextrin with mono-amino mono-carboxylic acids: physicochemical specification, characterization and molecular modeling.

Density (ρ), viscosity (η) and surface tension (γ) of three amino acids (valine, alanine, and glycine) have been measured at a different mass fraction (0.002 - 0.009) of aqueous hydroxypropyl-ß-cyclodextrin (HPßCD) mixtures and different temperatures (278.15 - 295.15 K). The formation of inclusion complexes has been analyzed via evaluating the amounts of apparent and limiting apparent molar volumes, limiting apparent molar expansibilities, activation energy, kinematic, relative, intrinsic, spatial, and dynamic viscosities. The surface tension studies indicated that the inclusion complexes have been formed with 1:1 stoichiometry and mediated by hydrophobic effects and electrostatic forces. Additionally, the ρ and η parameters were evaluated by molecular modeling experiments to provide more details on the mechanisms of the complexation.

Detailed chemical characterization and molecular modeling of serotonin inclusion complex with unmodified ß-cyclodextrin.

In this study, we analyzed the capability of unmodified ß-cyclodextrin (ß-CD) to form the stable complex with serotonin hydrochloride (SER), as an important neurotransmitter in the brain. The stable ß-CD: SER formulation was prepared and characterized using spectroscopic, thermal, molecular docking, and molecular dynamics techniques, revealing the phenomenon of H-bond formations and the domination of hydrophobic forces between the host molecule and its guest via the amine group of SER and the narrow side of ß-CD. The complexation mechanism was mainly enthalpy-driven, representing the improvement in SER photo-stability. Overall, the results highlighted the possibility to use this formulation with improved stability in clinical practice for treatment and prevention of various depressive conditions, such as anxiety disorders.

Binding assessment of two arachidonic-based synthetic derivatives of adrenalin with ß-lactoglobulin: Molecular modeling and chemometrics approach.

A computational approach to predict the main binding modes of two adrenalin derivatives, arachidonoyl adrenalin (AA-AD) and arachidonoyl noradrenalin (AA-NOR) with the ß-lactoglubuline (BLG) as a nano-milk protein carrier is presented and assessed by comparison to the UV-Vis absorption spectroscopic data using chemometric analysis. Analysis of the spectral data matrices by using the multivariate curve resolution-alternating least squares (MCR-ALS) algorithm led to the pure concentration calculation and spectral profiles resolution of the chemical constituents and the apparent equilibrium constants computation. The negative values of entropy and enthalpy changes for both compound indicated the essential role of hydrogen bonding and van der Waals interactions as main driving forces in stabilizing protein-ligand complex. Computational studies predicted that both derivatives are situated in the calyx pose and remained in that pose during the whole time of simulation with no any significant protein structural changes which pointed that the BLG could be considered as a suitable carrier for these catecholamine compounds.

Computational design of Tryprostatin-A derivatives as novel αß-tubulin inhibitors.

In the first part of this work, binding energies, inhibition constants and binding modes for a group of previously synthesized Tryprostatin-A (TPS-A) derivatives at the binding site of αß-tubulin have been comprehensively investigated by molecular docking study. The results represent relatively suitable binding energies for these inhibitors in the αß-tubulin binding site. In the second part, docking tools were utilized in order to design a group of novel analogues of TPS-A. The results of molecular docking reveal that these newly designed molecules have relatively lower binding energies in the pocket of αß-tubulin. Compound 26 resulted as the best docked molecule with the highest binding affinity (binding energy of -10.74 kcal/mol and calculated inhibition constant of 13.44 nM). In the last part of this study, three representative complexes were subjected to a 25 ns molecular dynamics simulation to further validate the proposed binding modes and interactions. Analysis of the simulation trajectories showed that the root mean square deviation (RMSD) profile of compound 26 was fairly stable during the whole simulation time, indicating that the orientation generated from the docking study is fairly well preserved during the entire length of the simulation. Moreover, the RMSD profiles of compounds 4 and 31 were probably stable in relation to αß-tubulin after 7 and 14 ns, and these molecular systems were well behaved thereafter. The results of the current study shed some light on the binding mode of TPS-A analogues for further experimental studies.

Characterization of modified magnetite nanoparticles for albumin immobilization.

Magnetite Fe3O4 nanoparticles (NPs) were prepared by chemical coprecipitation method. Silica-coated magnetite NPs were prepared by sol-gel reaction, subsequently coated with 3-aminopropyltriethoxysilane (APTES) via silanization reaction, and then were activated with 2,4,6-trichloro-1,3,5-triazine (TCT) and covalently immobilized with bovine serum albumin (BSA). The size and structure of the particles were characterized by transmission electron microscopy (TEM), X-ray powder diffraction (XRD), and dynamic light scattering (DLS) techniques. The immobilization was confirmed by Fourier transform infrared spectroscopy (FT-IR). XRD analysis showed that the binding process has not done any phase change to Fe3O4. The immobilization time for this process was 4 h and the amount of immobilized BSA for the initial value of 1.05 mg BSA was about 120 mg/gr nanoparticles. Also, the influences of three different buffer solutions and ionic strength on covalent immobilization were evaluated.

In vitro antitumor activity of parent and nano-encapsulated mono cobalt-substituted Keggin polyoxotungstate and its ctDNA binding properties.

The parent and nanosized starch, and lipid encapsulated K6[SiW11O39Co(H2O)]·nH2O (abbreviated as SEP, LEP and SiW11Co, respectively), as potent antitumor candidates, were synthesized and characterized by FT-IR spectroscopy, ICP, TG analysis, SEM and TEM images. The results show that the SiW11Co retains its parent structure after encapsulation by starch and lipid nanoparticles. Antitumor activity tests of SiW11Co and its encapsulated forms were carried out on two types of human cancer cells, MCF-7 and HEK-293 by MTT method. The encapsulated forms exhibited the higher antitumor activity compared to the parent SiW11Co. However, this observed enhancement for the lipid encapsulated form is more than the starch counterpart, which can be related to its smaller size. These results showed that these compounds can be novel antitumor candidates. The calf thymus DNA (abbreviated as ctDNA) binding ability of SiW11Co was also investigated, using UV-Vis absorption spectroscopy, fluorescence quenching and fluorescence Scatchard plots. Absorption spectra tracing reveal 10% hyperchromism for SiW11Co. The values of 1.8×10(4) and 1.2×10(4)M(-1) were obtained for association binding constant of SiW11Co to ctDNA at R⩾1 and R<1, respectively (R is defined as the mole ratio of SiW11Co to ctDNA). It was shown that the interaction of SiW11Co with ctDNA depended on the R values. The obtained results of absorption titration rejected the intercalating binding mode and suggest the groove or outside stacking binding for SiW11Co. These results were authenticated by fluorescence quenching experiments and scatchard plots.

ctDNA binding affinity and in vitro antitumor activity of three Keggin type polyoxotungestates.

The ctDNA-binding properties and in vitro antitumor activity of three water soluble Keggin type polyoxometalates (POMs): K6H[CoW11O39CpZr]·nH2O, K6H[CoW11O39CpTi·nH2O and K7H2[CoW11O39CpFe]·nH2O (abbreviated as CoWCpZr, CoWCpTi and CoWCpFe, respectively) were investigated using UV-Vis absorption spectroscopy, fluorescence spectrophotometry, cyclic voltammetry and MTT assay. The results of UV-Vis, fluorescence and cyclic voltammetry rule out intercalating binding mode and propose the groove or outside stacking binding of these POMs with ctDNA. The values of 1.30×10(4) M(-1), 1.15×10(4) M(-1) and 3.10×10(3) M(-1) were obtained for binding constant of CoWCpZr, CoWCpTi and CoWCpFe to ctDNA, respectively. The redox potential of POMs shift to more negative values in the presence of ctDNA which can be related to domination of electrostatic interaction in this system. The antitumor activity tests of these polyoxometalates (POMs) were carried out on two types of human cancer cells, MCF-7 and HEK-293 by MTT method. The results show the higher antitumor activity of CoWCpFe respect to two other that is related to its highest penetrating effectiveness for MCF-7 cells. Therefore, the antitumor activity of these POMs depends not only on their affinity to ctDNA but also strongly on their penetration ability to the cell membrane.

A combined spectroscopic, docking and molecular dynamics simulation approach to probing binding of a Schiff base complex to human serum albumin.

The molecular mechanism of a Schiff base complex ((E)-((E)-2-(3-((E)-((E)-3(mercapto (methylthio) methylene)cyclopentylidene) amino) propylimino) cyclopentylidene) (methylthio) methanethiol) binding to Human Serum Albumin (HSA) was investigated by fluorescence quenching, absorption spectroscopy, molecular docking and molecular dynamics (MD) simulation procedures. The fluorescence emission of HSA was quenched by this Schiff base complex that has been analyzed for estimation of binding parameters. The titration of Schiff base solution by various amount of HSA was also followed by UV-Vis absorption spectroscopy and the corresponding data were analyzed by suitable models. The results revealed that this Schiff base has an ability to bind strongly to HSA and formed 1:1 complex. Energy transfer mechanism of quenching was discussed and the value of 5.45 ± 0.06 nm was calculated as the mean distance between the bound complex and the Trp residue. This is implying the high possibility of energy transfer from HSA to this Schiff base complex. Molecular docking results indicated that the main active binding site for this Schiff base complex is site III in subdomain IB. Moreover, MD simulation results suggested that this Schiff base complex can interact with HSA, without affecting the secondary structure of HSA but probably with a slight modification of its tertiary structure. MD simulations, molecular docking and experimental data reciprocally supported each other.

Analysis of ligand binding process using binding capacity concept.

Binding capacity is the homotropic second derivative of the binding potential with respect to the chemical potential of the ligand. It provides a measure of steepness of the binding isotherm and represents the extent of cooperativity. In the present study, the shape of the binding capacity curve for various systems was investigated and the relation between binding capacity and the extent of cooperativity examined. In this regard, a novel linear graphical method was introduced for binding data analysis. The stoichiometry of binding and the extent of cooperativity can be determined by this method. This method has been successfully applied to various systems such as binding of oxygen to hemoglobin, warfarin to human serum albumin and dodecyltrimethylammonium bromide to alpha-amylase.

Mechanism of denaturation of bovine serum albumin by dodecyl trimethylammonium bromide.

Bovine serum albumin (BSA) denaturation has been extensively studied by different anionic and cationic surfactant. Dodecyl trimethylammonium bromide (DTAB) is a cationic surfactant, and it is suggested that it binds to the C-terminal section of BSA. In the present study, the thermodynamical denaturation of BSA by dodecyl trimethylammonium bromide (DTAB) has been studied with various experimental techniques. Equilibrium dialysis, thermal denaturation, gel electrophoresis, titration microcalorimetry at pH 7, I = 0.005, and different temperatures were all performed. The enthalpy obtained from the van't Hoff relation and calorimetry method as well as electrophoresis results were utilized to explain the BSA tranistion state. Major findings included: the binding isotherm shifts at a low free concentrations of DTAB and at a higher temperature suggest endothermicity for enthalpy of interaction; the calorimetry enthalpy (delta Hcal) of interaction was smaller than the van't Hoff enthalpy (delta HvH) for BSA-DTAB interaction; and the aggregation of BSA increased with increasing DTAB concentration. This study suggests that BSA unfolding induced by DTAB follows a multistate transition model and does not follow the two-state mechanism assumed for most single subunit proteins.