A finite-size scaling study of a model of globular proteins

Grand canonical Monte Carlo simulations are used to explore the metastable fluid-fluid coexistence curve of the modified Lennard-Jones model of globular proteins of ten Wolde and Frenkel [Science, 277, 1975 (1997)]. Using both mixed-field finite-size scaling and histogram-reweighting methods, the joint distribution of density and energy fluctuations is analyzed at coexistence to accurately determine the critical-point parameters. The subcritical coexistence region is explored using the recently developed hyper parallel tempering Monte Carlo simulation method along with histogram reweighting to obtain the density distributions. The phase diagram for the metastable fluid-fluid coexistence curve is calculated in close proximity to the critical point, a region previously unattained by simulations.     

A comparative DFT study of some N-based aromatic ligand metal complexes as anticancer agents and analysis of their mode of interaction with DNA base pair

Metal complexed anticancer agents interact with DNA nucleobase pairs (AT and GC) through different types of binding mode such as intercalation, groove binding, covalent binding, etc. Minor and major groove binding mechanism of DNA base pair is the key factor for all kinds of anticancer agent; as metal complexes have a great affinity to bind with DNA nucleobase either through minor or major groove. Ligands in metal complexes also play a vital role during the interaction with DNA base pairs; these ligands directly interact with DNA through different interacting modes. Generally, anticancer agents with less sterically hindered N-based aromatic and planar ligands are the key component for DNA binding; as the structure of such ligands are quite compatible for following intercalation and groove binding mechanism. Since, the experimental investigation for drug-DNA nucleobase complexes are extremely complicated, therefore; quantum mechanical calculations might be very helpful for computing the actual interactions in drug-DNA complexes. Quantum mechanical approaches such as density functional theory (DFT) might be a very important and useful tool to investigate the actual mode of interaction of metal complexed antitumor agents with DNA nucleobase. Herein, we have taken some metal complexes with N-based aromatic ligands as antitumor agents to investigate the proper mode of interaction between drug-DNA complexes.     

Effect of electrostatic interaction on the adsorption of globular proteins on octacalcium phosphate crystal film

The electrostatic effect on the adsorption of globular proteins, such as bovine serum albumin (BSA), hen egg white lysozyme (LZM), and beta-lactoglobulin (beta-Lg), on octacalcium phosphate (OCP)-like crystal thin films was investigated. A poorly crystalline thin film was synthesized on a tissue culture polystyrene (TCP) surface and used as a model surface in this study. The solution pH clearly affected the electrostatic properties of both proteins and surface. The adsorbed amounts obtained at quasi-steady state were readily related to the solution pH for each protein. The adsorption rate is fast during the initial period and levels off gradually. The maximum adsorbed mass occurred at pH 7 for BSA and at pH 9 for LZM. beta-Lg adsorbed similar amounts at pHs lower than 9, but the adsorbed mass decreased at pHs higher than 9 where electrostatic repulsion exists. The pH values where the maximum adsorbed mass occurred may be considered as the conditions where electrostatic attraction is most favorable. The adsorbed mass of beta-Lg was the greatest among the proteins of interest while BSA adsorbed the least despite its greater molecular mass. LZM falls into the intermediate region. According to these observations, BSA has undergone conformational changes that prevent further adsorption to a greater extent than the others. A simple relationship between the adsorption rate and the electrostatic properties was not established. However, the order of magnitude of the adsorption rate at the initial period tends to be the same as that of maximum adsorbed mass for each protein.     

Combination of chelating behaviour with molecular recognition as interaction for ligand exchange chromatography

A novel chelating resin was synthesized, composed of chemically bonded glycinocyclodextrin (S-CD-G) to which silica gel was added as matrix and silanes with amino groups as spacer. It showed efficient complexation with transition metal cations. In this report the copper and zinc resin complexes were investigated for application as stationary phases for the separation of substituted phenol isomers. The results revealed that the copper resin complex has a high potential for this application.     

Binding interaction of cationic phenazinium dyes with calf thymus DNA: a comparative study

Absorption, steady-state fluorescence, steady-state fluorescence anisotropy, and intrinsic and induced circular dichroism (CD) have been exploited to explore the binding of calf thymus DNA (ctDNA) with three cationic phenazinium dyes, viz., phenosafranin (PSF), safranin-T (ST), and safranin-O (SO). The absorption and fluorescence spectra of all the three dyes reflect significant modifications upon interaction with the DNA. A comparative study of the dyes with respect to modification of fluorescence and fluorescence anisotropy upon binding, effect of urea, iodide-induced fluorescence quenching, and CD measurements reveal that the dyes bind to the ctDNA principally in an intercalative fashion. The effect of ionic strength indicates that electrostatic attraction between the cationic dyes and ctDNA is also an important component of the dye-DNA interaction. Intrinsic and induced CD studies help to assess the structural effects of dyes binding to DNA and confirm the intercalative mode of binding as suggested by fluorescence and other studies. Finally it is proposed that dyes with bulkier substitutions are intercalated into the DNA to a lesser extent.     

'Inductive' charges on atoms in proteins: comparative docking with the extended steroid benchmark set and discovery of a novel SHBG ligand

We have developed a novel iterative approach for calculation of partial charges in proteins within the framework of the 'molecular capacitance' model. The method operates by an effective 'inductive' electronegativity scale derived from a number of the conventional charge systems including CHARMM, AMBER, MMFF, OPLS, and PEOE among others. Our novel 'inductive' electronegativity equalization procedure allows rapid and conformation sensitive computation of adequate partial charges in proteins. Accuracy of the 'inductive' values was confirmed by their correlation with DFT-computed partial charges in common amino acids. A comparative docking study with an extended steroid data set not only illustrated the adequacy of 'inductive' protein charges but also demonstrated their superior performance compared to several conventional protein charging systems. Subsequent docking with 'inductive' charges resulted in identification of five potential leads as human Sex Hormone Binding Globulin (SHBG) ligands from a commercial library of natural compounds. When the selected substances were evaluated for their ability to bind SHBG in vitro, three of them displaced testosterone from the SHBG steroid-binding site, and with one compound this was achieved at micromolar concentrations.     

Quantum-mechanical study of lead coordination in sulfur-rich proteins: mode and structure recognition in UV resonance Raman spectra

Resonance Raman spectra are computed applying the weighted gradient methodology with CIS and DFT gradients to determine the characteristic spectral patterns for Hg(II) and Pb(II) loaded sulfur-rich proteins while excited to a characteristic LMCT electronic transition band. A framework of structure-spectrum relationships is established to assess lead coordination modes via vibrational spectroscopy. Illustrative calculations on Hg(II) complexes agree with experimental data demonstrating reliability and accuracy of the applied methodology. In contrast to Hg(II) complexes, a unique 3-center-4-electron hypervalent C(β)H···S interaction present in lead-sulfur complexes was established and suggested to play a key role in the strong preference for lead versus other metal ions in lead specific proteins such as PbrR691. The characteristic Pb-S symmetric stretching bands, predicted without additional refinements such as scaling of a force field or frequencies, are found around 238 cm(-1) for 3-coordinated lead-sulfur domains and around 228 cm(-1) for 4-coordinated lead-sulfur domains. These results present an experimental challenge for clear detection of lead coordination via solely UVRR spectroscopy. In addition to predicted UVRR spectra, UVRR excitation profiles for relevant vibrational bands of lead-sulfur domains are presented.     

A comparative study of interaction of ibuprofen with biocompatible polymers

In this paper we are reporting the interaction of a non-steroidal anti-inflammatory drug ibuprofen (IBF) with various biocompatible polymers. Being amphiphilic, the drug interacts with the polymers similar to the interaction of surfactants and polymers. Therefore, we have considered the polymer-amphiphile interaction approach using conductimetry. The polymers of different charges (cationic, anionic, and nonionic) have been taken for the study. It was found that the critical aggregation concentration (cac) decreases on increasing the polymer concentrations of cationic as well as nonionic polymers whereas it increases for anionic polymers. The results imply that anionic IBF interacts with cationic and nonionic polymers more strongly as compared to the anionic polymers. A possible anionic-anionic repulsion is responsible for the weak interaction of IBF with anionic polymers. On the other side, the critical micelle concentration (cmc) increases for all polymers which is a usual indication of the interaction between amphiphiles and polymers. Free energies of aggregation (ΔG_agg) and micellization (ΔG_mic) were also computed with the help of degrees of micelle ionization obtained from the specific conductivity - [IBF] isotherms.     

A comparative study on the mode of interaction of different nanoparticles during MALDI‐MS of bacterial cells

We propose the benefits of preincubation during nanoparticle‐assisted bacterial analysis, where the bacteria are grown along with the nanoparticles. We were able to obtain a two to ten fold enhancement of bacterial signals in 3 h compared to the generally used methodology followed in previous literature. The previous literature method required a long time (18 h) to obtain such an enhancement. We probe the interactions of two bacteria, Staphylococcus aureus and Pseudomonas aeruginosa, with Ag, NiO, Pt TiO₂ and ZnO nanoparticles via transmission electron microscopy, ultraviolet spectroscopy and matrix‐assisted laser desorption/ionization (MALDI) mass spectrometry (MS). Based on these results, we propose a mechanism for interaction of these five nanoparticles with bacteria. Two mechanisms were observed for the interactions: (1) Mechanism A is proposed for the Pt and NiO NPs which functioned based on affinity for bacterial cells. (2) Mechanism B was proposed for the bactericidal NPs such as TiO₂, ZnO and Ag NPs. The results indicate that the success of the unmodified NPs in MALDI‐MS bacterial studies lies in following the ideal protocol for incubation at the ideal concentrations. Copyright © 2013 John Wiley & Sons, Ltd.     

Sequence design of biomimetic copolymers: modeling of membrane proteins and globular proteins with active enzymatic center

The biomimetic approach to the sequence design of synthetic AB‐copolymers has been developed further by means of new series of Monte Carlo computer simulation. The approach is based on using of some particular conformation of a homopolymer chain for “coloring” of monomeric units into two “colors” (or types) A and B depending on the spatial position of particular monomeric unit. We present recent data of our Monte Carlo computer simulation studies of properties of designed AB‐copolymers which mimic membrane proteins, and designed ABC‐copolymers which mimic proteins with active enzymatic center. We have found further evidences for the fact that designed copolymer chain preserves the “memory” about its “parent” spatial conformation and shows the well‐pronounced tendency to restore main features of the “parent” conformation.     

Unraveling the nature of the segmentation clock: Intrinsic disorder of clock proteins and their interaction map

Vertebrate segmentation has been proved to be under a strict temporal control governed by a biological clock, known as the segmentation clock. The present experimental evidence suggests that the segmentation clock initiates and maintains its periodic cycle by the periodic activation or inhibition of the Notch signaling pathway as well as the periodic autoregulation of the cyclic genes themselves. In this paper, we investigate the structural and evolutionary properties of the Notch pathway proteins involved in the mice segmentation clock and computationally identify the interaction map within the Notch signaling pathway. The results of our analysis strongly indicate that most of the pathway proteins are intrinsically disordered and that the mechanism of their interaction likely involves helical molecular recognition elements, short loosely structured segments within disordered regions which are directly involved in protein-protein interactions. Predicted interactions are in agreement with gene knock-out studies available in the literature.     

Prediction of the interaction of metallic moieties with proteins: An update for protein‐ligand docking techniques

In this article, we present a new approach to expand the range of application of protein‐ligand docking methods in the prediction of the interaction of coordination complexes (i.e., metallodrugs, natural and artificial cofactors, etc.) with proteins. To do so, we assume that, from a pure computational point of view, hydrogen bond functions could be an adequate model for the coordination bonds as both share directionality and polarity aspects. In this model, docking of metalloligands can be performed without using any geometrical constraints or energy restraints. The hard work consists in generating the convenient atom types and scoring functions. To test this approach, we applied our model to 39 high‐quality X‐ray structures with transition and main group metal complexes bound via a unique coordination bond to a protein. This concept was implemented in the protein‐ligand docking program GOLD. The results are in very good agreement with the experimental structures: the percentage for which the RMSD of the simulated pose is smaller than the X‐ray spectra resolution is 92.3% and the mean value of RMSD is < 1.0 Å. Such results also show the viability of the method to predict metal complexes–proteins interactions when the X‐ray structure is not available. This work could be the first step for novel applicability of docking techniques in medicinal and bioinorganic chemistry and appears generalizable enough to be implemented in most protein‐ligand docking programs nowadays available. © 2017 Wiley Periodicals, Inc.     

Biarylpyrimidines: a new class of ligand for high-order DNA recognition

Biarylpyrimidines bearing omega-aminoalkyl substituents have been designed as ligands for high-order DNA structures: spectrophotometric, thermal and competition equilibrium dialysis assays showed that changing the functional group for substituent attachment from thioether to amide switches the structural binding preference from triplex to tetraplex DNA; the novel ligands are non-toxic and moderate inhibitors of human telomerase.     

Hydrophobic interaction electrophoresis under high hydrostatic pressure: study of the effects of pressure upon the interaction of serum albumin with a long-chain aliphatic ligand

Hydrophobic affinity electrophoresis under high hydrostatic pressure has been developed to study the interaction between fatty acid-free bovine serum albumin and a long-chain aliphatic ligand physically immobilized within the gel matrix. From apparent association constants at various pressures and temperatures, apparent thermodynamic parameters including the volume change in binding were calculated. The results are as expected for hydrophobic interactions between the long-chain alkyl ligand and a high-affinity long-chain fatty acid binding site. The feasibility of high-pressure affinity electrophoresis is demonstrated. This new high-pressure technique provides a direct means for studying quantitatively the effects of pressure upon protein-ligand interactions. It could become a suitable tool for the investigation of protein binding sites' topography.     

Non-convertional hydrogen bonding interaction of BH3NH3 complexes: a comparative theoretical study

A new type of hydrogen bond, called a dihydrogen bond, has recently been introduced. In this bond hydrogen is donated to (hydridic) hydrogen. In this paper, ab initio HF, MP2 and DFT(B3LYP) levels of theory with different basis sets in combination with counterpoise procedure for basis set superposition error correction have been applied to BH₃NH₃ dimer and BH₃NH₃ complexes of methane, hydrogen cyanide, ammonia, water, methanol and hydrogen fluoride to understand the features of dihydrogen bond. The optimized geometric parameters and interaction energies for various isomers at different levels are estimated. The structures obtained at different computational levels are in agreement with each other. Dihydrogen bond does not occur in both BH₃NH₃⋯CH₄ and BH₃NH₃⋯NH₃ complexes. Apart from the B–H⋯H–N dihydrogen bond found in the BH₃NH₃ crystal and dimmer, the B–H⋯H–X (XC, O, F) dihydrogen bonds have been observed in the BH₃NH₃⋯HCN, BH₃NH₃⋯H₂O, BH₃NH₃⋯CH₃OH and BH₃NH₃⋯HF complexes, while the classic H bonds also exist in the last three complexes. As for the complexes in which only dihydrogen bonds appear the strength of dihydrogen bonds ranges from 17.9 to 18.9 kJ mol⁻¹ at B3LYP/6-311++g(d,p) level. Binding energies obtained from the MP2 and B3LYP optimized structures are more sensitive to basis sets than those from the HF method. Larger basis functions generally tend to produce slightly longer intermolecular distances, and the B3LYP and MP2 methods generate shorter intermolecular distances though they usually produce longer bond lengths compared with those at the HF level. The infrared spectrum frequencies, IR intensities and the vibrational frequency shifts are reported. Finally the solution phase studies on BH₃NH₃⋯HF complex are also carried out using the Onsager reaction field model with a range of dielectric constants from 2 to 80 at B3LYP/6-311++g(d,p) level.     

Glycine interaction with carbon nanotubes: an ab initio study

The interaction of the glycine radical on the side walls of both armchair and zigzag single walled carbon nanotubes is investigated by density functional theory. It is found that the interaction potential of the N-centered glycine radical with the tubes has a minimum of 16.9 (armchair) and 20.2 (zigzag) kcal/mol with respect to the dissociation products. In contrast, the C-centered radical, which is 22.7 kcal/mol lower in energy than the N-centered radical, does not form stable complexes with both types of carbon nanotubes.     

Binding of an acetic acid ligand to adenosine: a low-temperature NMR study

Binding of an acetic acid (HAc) ligand to adenosine (A) was studied by (1)H NMR spectroscopic techniques. Using a low-melting deuterated Freon mixture as solvent, liquid-state measurements could be performed in the slow exchange regime and allowed a detailed characterization of the formed associates. Thus, at 128 K, trimolecular complexes A.HAc(2) and A(2).HAc with both Watson-Crick and Hoogsteen sites of the central adenine base occupied coexist in various amounts depending on the adenosine:acetic acid molar ratio. Whereas the carboxylic acid OH proton is located closer to the acid for all hydrogen bonds formed, a more deshielded proton at the Watson-Crick site is evidence for a stronger hydrogen bond as compared to the Hoogsteen interaction. For the binding of acetic acid to an adenosine-thymidine base pair in either a Watson-Crick or a Hoogsteen configuration, hydrogen bonds to the available adenine binding site are strengthened as compared to the corresponding hydrogen bonds in the A.HAc(2) complex.     

Probing the acetylcholinesterase inhibition of sarin: a comparative interaction study of the inhibitor and acetylcholine with a model enzyme cavity

Interaction energies have been estimated between sarin and a model enzyme cavity of acetylcholinesterase (ACHE) using the density functional and M?ller-Plesset second-order perturbation (MP2) levels of theories. The calculated interaction energies have been compared with those of acetylcholine and the same model ACHE cavity. The ACHE...sarin and ACHE...acetylcholine (Ach) structures have been optimized using DFT based two-layer ONIOM hybrid calculations. The nature of interactions has been investigated in detail using an interaction energy partitioning technique. The effects of solvation on the interaction energies have also been taken into account. An inhibition mechanism during the uptake of sarin inside the ACHE cavity has been proposed from the comparison of the energetics of the ACHE...sarin and ACHE...Ach complexes.