Molecular Recognition Interactions Research Articles

Controllable and large-scale supramolecular vesicle aggregation: orthogonal light-responsive host–guest and metal–ligand interactions

On the basis of the host–guest molecular recognition interaction between β-cyclodextrin and azobenzene, two kinds of supramolecular self-assemblies (Py-CD⊃Azo-C and Py-CD⊃Azo-C3) were constructed.

Exploring PfDHFR reaction surface: A combined molecular dynamics and QM/MM analysis

The substrate to the enzyme PfDHFR (Plasmodium falciparum Dihydrofolate Reductase) is a small molecule dihydrofolate (DHF), it gets converted to tetrahydrofolate (THF) in the active site of the enzyme. The PfDHFR reaction surface involves the protonation of DHF to DHFP as an initial step before the catalytic conversion. The binding affinities of all these species (DHF, DHFP and THF) contribute to the mechanism of DHFR catalytic action. Molecular dynamics (MD) simulations and Quantum Mechanics/Molecular Mechanics (QM/MM) analysis were performed to evaluate the binding affinity and molecular recognition interactions of the substrate DHF/DHFP and the product THF, in the active site of wild-type PfDHFR (wtPfDHFR). The binding affinities of the cofactor NADPH/NADP+ were also estimated in all the three complexes. The molecular dynamics (MD) simulations of the substrate, product and cofactor in the cavities of wtPfDHFR revealed the variation of the atomic level interactions during the course of the catalytic conversion. It was found that the DHFP binds very strongly to the PfDHFR active site and pulls the cofactor NADPH closer to itself. The QM/MM analysis revealed that the binding energy of DHFP (−59.82 kcal/mol) and NADPH (−100.24 kcal/mol) in DHFP-wtPfDHFR complex, is higher in comparison to the binding energy of DHF (−38.67 kcal/mol) and NADPH (−77.53 kcal/mol) in DHF-wtPfDHFR complex and the binding energy of THF (−30.72 kcal/mol) and NADP+ (−73.72 kcal/mol) in THF-wtPfDHFR complex. The hydride ion donor-acceptor distance (DAD) analysis was also carried out. This combined MD and QM/MM analysis revealed that the protonation of DHF increases the proximity between the substrate and the cofactor, thus facilitates the reaction profile of PfDHFR.

Pharmacoinformatics analysis of merbarone binding site in human topoisomerase IIα

Merbarone is a derivative of thiobarbituric acid, possessing catalytic inhibitory potential against human topoisomerase IIα (hTopoIIα). Merbarone was reported to inhibit DNA cleavage by hTopoIIα. It is important to understand the molecular mechanism of hTopoIIα inhibition by merbarone, as these details guide the rational design of new ligands. In this work, a systematic pharmacoinformatics analysis has been reported to analyze the merbarone-hTopoIIα interactions and to identify merbarone analogs as potential hTopoIIα inhibitors. The reported crystal structure of hTopoIIα-DNA complex (PDB ID: 4FM9) is not suitable for analyzing the merbarone-binding domain, because it is a biological assembly of hTopoIIα in C-gate open conformation. Therefore, 3D structure of hTopoIIα-DNA complex suitable for molecular modeling analysis at merbarone binding site was first generated. Using this generated complex, molecular docking analysis and molecular dynamics simulations were performed to explore the effect of merbarone on hTopoIIα-DNA complex. The binding energy for the enol form of merbarone with hTopoIIα-DNA was estimated to be −51.28 kcal/mol. The explored binding site and identified molecular recognition interactions were in accordance with the previously reported interference in the DNA-cleavage by merbarone. Virtual screening was performed using drug likeness filters, toxicity filters and ADMET descriptor based filters followed by molecular docking (ZINC database). Sixteen compounds were identified as merbarone-functional analogs suitable for hTopoIIα inhibition. These identified molecules can be considered for further evaluation of their anti-hTopoIIα activity.

π-Cation Interactions in Molecular Recognition: Perspectives on Pharmaceuticals and Pesticides.

The π-cation interaction that differs from the cation-π interaction is a valuable concept in molecular design of pharmaceuticals and pesticides. In this Perspective we present an up-to-date review (from 1995 to 2017) on bioactive molecules involving π-cation interactions with the recognition site, and categorize into systems of inhibitor-enzyme, ligand-receptor, ligand-transporter, and hapten-antibody. The concept of π-cation interactions offers use of π systems in a small molecule to enhance the binding affinity, specificity, selectivity, lipophilicity, bioavailability, and metabolic stability, which are physiochemical features desired for drugs and pesticides.

分子識別における弱い相互作用の役割 : 不斉反応と生体分子の特異性( 化学における弱い相互作用)

分子識別における弱い相互作用の役割 : 不斉反応と生体分子の特異性( 化学における弱い相互作用)

Molecular recognition and binding of beta-lactamase II from Bacillus cereus with penicillin V and sulbactam by spectroscopic analysis in combination with docking simulation.

The molecular recognition and binding interaction of beta-lactamase II from Bacillus cereus (Bc II) with penicillin V (PV) and sulbactam (Sul) at 277K were studied by spectroscopic analysis and molecular docking. The results showed that a non-fluorescence static complex was separately formed between Bc II and two ligands, the molecular ratio of Bc II to PV or Sul was both 1:1 in the binding and the binding constants were 2.00×106 and 3.98×105 (L/mol), respectively. The negative free energy changes and apparent activation energies indicated that both the binding processes were spontaneous. Molecular docking showed that in the binding process, the whole Sul molecule entered into the binding pocket of Bc II while only part of the whole PV molecule entered into the pocket due to a long side chain, and electrostatic interactions were the major contribution to the binding processes. In addition, a weak conformational change of Bc II was also observed in the molecular recognition and binding process of Bc II with PV or Sul. This study may provide some valuable information for exploring the recognition and binding of proteins with ligands in the binding process and for the design of novel super-antibiotics.

An in-silico approach to find a peptidomimetic targeting extracellular domain of HER3 from a HER3 Nanobody

HER3 is an important therapeutic target in cancer treatments. HER3 Nanobodies (Nbs) are a novel class of antibodies with several competitive advantages over conventional antibodies. A peptidomimetic derived from these Nbs can be considered to be a small peptide mimicking some of the molecular recognition interactions of a natural peptide or protein in a three-dimensional (3D) space, with a receptor that has improved properties.In this study, we introduce a new approach to design a peptidomimetic derived from HER3 Nb through an in silico analysis. We propose that the complementarity determining region (CDR3) of HER3 Nb is large enough to effectively interact with HER3 antigen as well as with the entire Nb. A computational analysis has been performed using Nb models retrieved from SWISS-pdb Viewer 4.1.0 (spdbv) as a target spot and HER3 extracellular domain as its antigenic target to identify the interactions between them by the protein–protein docking method. Detailed analysis of selected models with docked complex help us to identify the interacting amino acid residues between the two molecules. The results of in silico analysis show that the CDR3 of HER3 Nb might be used by itself as a peptidomimetic drug instead of the full Nb. HER3 peptidomimetic-derived HER3 Nb may reduce Nb production costs and be used as a substitute for HER3 Nb after further experimental work. The paper demonstrates the feasibility of peptidomimetics designs using bioinformatic tools.

Mineralization Process of Biocemented Sand and Impact of Bacteria and Calcium Ions Concentrations on Crystal Morphology

Microbial-induced calcite precipitation (MICP) is a sustainable technique used to improve sandy soil. Analysis of the mineralization process, as well as different bacterial suspensions and calcium concentrations on the crystal morphology, revealed that the mineralization process included four stages: self-organised hydrolysis of microorganisms, molecular recognition and interface interaction, growth modulation, and epitaxial growth. By increasing bacterial suspensions and calcium concentrations, the crystal morphology changed from hexahedron to oblique polyhedron to ellipsoid; the best crystal structure occurs at OD600 = 1.0 and [Ca2+] = 0.75 mol/l. It should be noted that interfacial hydrogen bonding is the main force that binds the loose sand particles. These results will help in understanding the mechanism of MICP.

The Limit of Intramolecular H-Bonding.

Hydrogen bonds are ubiquitous interactions in molecular recognition. The energetics of such processes are governed by the competing influences of pre-organization and flexibility that are often hard to predict. Here we have measured the strength of intramolecular interactions between H-bond donor and acceptor sites separated by a variable linker. A striking distance-dependent threshold was observed in the intramolecular interaction energies. H-bonds were worth less than -1 kJ mol-1 when the interacting groups were separated by ≥6 rotating bonds, but ranged between -5 and -9 kJ mol-1 for ≤5 rotors. Thus, only very strong external H-bond acceptors were able to compete with the stronger internal H-bonds. In addition, a constant energetic penalty per rotor of ∼5-6 kJ mol-1 was observed in less strained situations where the molecule contained ≥4 rotatable bonds.

Hydration Dynamics of a Peripheral Membrane Protein.

Water dynamics in the hydration shell of the peripheral membrane protein annexin B12 were studied using MD simulations and Overhauser DNP-enhanced NMR. We show that retardation of water motions near phospholipid bilayers is extended by the presence of a membrane-bound protein, up to around 10 Å above that protein. Near the membrane surface, electrostatic interactions with the lipid head groups strongly slow down water dynamics, whereas protein-induced water retardation is weaker and dominates only at distances beyond 10 Å from the membrane surface. The results can be understood from a simple model based on additive contributions from the membrane and the protein to the activation free energy barriers of water diffusion next to the biomolecular surfaces. Furthermore, analysis of the intermolecular vibrations of the water network reveals that retarded water motions near the membrane shift the vibrational modes to higher frequencies, which we used to identify an entropy gradient from the membrane surface toward the bulk water. Our results have implications for processes that take place at lipid membrane surfaces, including molecular recognition, binding, and protein-protein interactions.

Optimized method for TAG protein homology modeling: In silico and experimental structural characterization

The DNA glycosylases cleave CN glycosyl bond to release a free base and generate abasic sites concurrently. Function and structure of these enzymes in the pathogenic bacterium Acinetobacter baumannii and its closely related species are not well characterized. Inhibition of TAG enzyme is a promising drug design strategy against A. baumannii. Here optimized molecular modeling approaches were used to provide a structural scaffold of TAG. The recombinant TAG protein was expressed and purified to determine oligomeric state using size exclusion chromatography, which showed the existence of TAG protein as monomer (mwt ⿼21kDa). Secondary structure and substrate binding were analyzed using CD are in good agreement with the in silico predictions. Near UV-CD spectrum shows the involvement of Tyr residues in substrate recognition. Molecular docking studies were performed to understand the molecular recognition interactions and this knowledge was used to identify the potent inhibitors using virtual screening. Residues crucial for DNA holding and enzyme catalysis are reconfirmed by the in silico mutational studies.

Recognition and binding of β-lactam antibiotics to bovine serum albumin by frontal affinity chromatography in combination with spectroscopy and molecular docking.

Serum albumins are the most abundant carrier proteins in blood plasma and participate in the binding and transportation of various exogenous and endogenous compounds in the body. This work was designed to investigate the recognition and binding of three typical β-lactam antibiotics including penicillin G (Pen G), penicillin V (Pen V) and cefalexin (Cef) with bovine serum albumin (BSA) by frontal affinity chromatography in combination with UV-vis absorption spectra, fluorescence emission spectra, binding site marker competitive experiment and molecular docking under simulated physiological conditions. The results showed that a BSA only bound with one antibiotic molecule in the binding process, and the binding constants for Pen G-BSA, Pen V-BSA and Cef-BSA complexes were 4.22×10(1), 4.86×10(2) and 3.32×10(3) (L/mol), respectively. All the three β-lactam antibiotics were mainly inserted into the subdomain IIA (binding site 1) of BSA by hydrogen bonds and Van der Waals forces. The binding capacity between the antibiotics and BSA was closely related to the functional groups and flexibility of side chains in antibiotics. This study provided an important insight into the molecular recognition and binding interaction of BSA with β-lactam antibiotics, which may be a useful guideline for the innovative clinical medications and new antibiotic designs with effective pharmacological properties.

Structural insight into the reaction mechanism of Pd-catalyzed nitrile hydration: Trapping the [Pd(H2O)4]2+ cation through a supramolecular complex

Four new bis(oxamato)palladate(II) complexes of formula (n-Bu4N)2[Pd(2,4,6-Me3pma)2]·2CH3CN (1), (n-Bu4N)2[Pd(2,4,6-Me3pma)2]·2CH3CONH2 (2) and (n-Bu4N)4[Pd(H2O)4][Pd(4-Xpma)2]3·2CH3CONH2 with X=Br (3) and Cl (4) (2,4,6-Me3pma=N-2,4,6-trimethylphenyloxamate, 4-Brpma=N-4-bromophenyloxamate, N-4-chlorophenyloxamate and n-Bu4N+=tetra-n-butylammonium) have been obtained and characterized by single crystal X-ray diffraction. All of them contain bis(oxamato)palladate(II) anions and bulky n-Bu4N+ cations, but compounds 3 and 4 have also the out of the ordinary [Pd(H2O)4]2+ inorganic cation. Acetonitrile and appealing acetamide are present as lattice molecules in compounds (1) and (2–4), respectively. While 1 was prepared in a neutral solution, species 2–4 were obtained in a basic medium. The acetamide molecules are the natural consequence of the acetonitrile hydration reaction during the oxamate-palladate(II) complexation. Interestingly, the use of a different oxamate ligand supports (through a molecular-recognition interaction) the structural grasping of the [Pd(H2O)4]2+ species, which can be considered as a reaction intermediate for the nitrile hydration.

Lignin as immobilization matrix for HIV p17 peptide used in immunosensing.

Immunosensors based on electrical impedance spectroscopy (EIS) are increasingly being used as a fast and potentially low cost method for clinical diagnostics. In this work we fabricated immunosensors by depositing layer-by-layer (LbL) films made with an antigenic peptide (p17-1) sequence (H2N-LSGGELDRWEKIRLRPGG-OH) and lignin on interdigitated gold electrodes, which could detect anti-p17 (HIV, human immune deficiency virus) antibodies (Ab) in phosphate buffered solutions (PBS). The molecular recognition interaction between the peptide (p17-1) and the specific Ab (anti-p17) yielded substantial changes in morphology of the with LbL films, with increased roughness according to atomic force microscopy data. This interaction is behind the high sensitivity of the immunosensor. Indeed, from the EIS results, we noted that the capacitance increased significantly with the specific Ab concentration, before getting close to saturation of available peptide sites at high concentrations. Concentrations of specific antibodies as low as 0.1 ng/mL could be detected and the immunosensors had their activity preserved for two months at least. The selectivity of the immunosensor was confirmed with two types of control experiments. First, no changes in impedance were observed when the lignin/peptide LbL immunosensor was immersed into a PBS solution containing the non-specific Ab (anti-HCV for Hepatitis C) antibodies. Furthermore, for sensing units made LbL films of lignin only, the electrical response was not affected by adding specific antibodies into the PBS buffer. The successful immunosensing for HIV with antigenic peptides in a lignin matrix is also relevant for valorization of lignin, which is an important biomass component in the sugar and ethanol industry, and brings the prospect for all-organic, biocompatible sensors if implantation is ever required.

Dielectrically Controlled Priority of Interactions in Molecular Recognition

It was shown previously that formation of brucinium double salts during attempts of racemic resolution of N-(3,5-dinitrobenzoyl)amino acid (alanine or serine) by fractional crystallization of brucinium diastereomeric salts is related to the self-recognition of anions of the amino acid derivatives into dimeric units stabilized by a set of hydrogen bonds (Bialonska, A. and Ciunik, A. Why Is the Resolution of Certain Racemic Modifications Inefficient? Formation of Diastereomeric Double Salts of Brucinium. Cryst. Growth Des. 2013, 13, 111−120). Similar dimeric units were observed in brucinium diastereomeric salts precipitated from methanol solutions containing brucine and one enantiomer of the amino acid derivative. To test if the ability of the anions to form dimeric units can be weakened, an increase of dielectric constant of solutions from which the brucinium salts precipitated was applied. In this approach, three new crystalline forms of brucinium salts with enantiomeric N-(3,5-dinitrobenzoyl)serine were ...

Structural basis of multivalent galactose-based dendrimer recognition by human galectin-7.

Galectins are evolutionarily conserved and ubiquitously present animal lectins with a high affinity for β-galactose-containing oligosaccharides. To date, 15 mammalian galectins have been identified. Their involvement in cell-cell and cell-matrix interactions has highlighted their importance in signal transduction and other intracellular processes. Human galectin-7 (hGal-7) is a 15 kDa proto type galectin that forms a dimer in solution and its involvement in the stimulation and development of tumour growth has been reported. Previously, we reported the crystal structure of hGal-7 and its complex with galactose and lactose which provided insight into its molecular recognition and detailed interactions. Here, we present newly obtained high-resolution structural data on carbohydrate-based dendrons in complex with hGal-7. Our crystallographic data reveal how multivalent ligands interact with and form cross-links with these galectin molecules. Understanding how these dendrimeric compounds interact with hGal-7 would help in the design of new tools to investigate the recognition of carbohydrates by lectins.

Molecule–Surface Recognition between Heterocyclic Aromatic Compounds and Kaolinite in Toluene Investigated by Molecular Theory of Solvation and Thermodynamic and Kinetic Experiments

Molecular recognition interactions between kaolinite and a series of heterocyclic aromatic compounds (HAC) representative of the N- and S-containing moieties in petroleum asphaltene macromolecules are investigated using the three-dimensional reference interaction site model with the Kovalenko–Hirata closure approximation (3D-RISM-KH) theory of solvation and experimental techniques in toluene solvent. The statistical-mechanical 3D-RISM-KH molecular theory of solvation predicts the adsorption configuration and thermodynamics from the 3D site density distribution functions and total solvation free energy, respectively, for adsorption of HAC and toluene on kaolinite. Spectrophotometric measurements show that, among the HAC studied, only acridine and phenanthridine adsorb quantitatively on kaolinite. For these pyridinic HAC, the adsorption results fitted to the Langmuir isotherm in the monolayer domain suggest a uniform monolayer of HAC molecules. The 3D-RISM-KH studies predict that the aluminum hydroxide surf...

Poly(N-isopropylacrylamide-co-tris-nitrilotriacetic acid acrylamide) for a combined study of molecular recognition and spatial constraints in protein binding and interactions.

Many biological processes require precise regulation and synergy of proteins, and consequently involve molecular recognition and spatial constraints between biomolecules. Here, a library of poly(N-isopropylacrylamide-co-tris-nitrilotriacetic acid acrylamide) (PNTs) has been synthesized and complexed with Cu(2+) in order to serve as models for investigation of the combined effects of molecular recognition and spatial constraints in biomolecular interactions. The average distance between Cu(2+)-trisNTA binding sites in PNTs polymers was varied from 4.3 to 31.5 nm by adjusting their trisNTA contents. His tag (His6), His-tagged enhanced yellow fluorescent protein (His6-eYFP), and His6-tagged collagenase G (His6-ColG), with sizes ranging from 1 to 11 nm, were used as models to assess whether the binding ability is influenced by a cooperative topology based on molecular recognition interactions with Cu(2+)-trisNTA binding sites, and spatial constraints created by decreasing average distance between trisNTAs. His-tagged molecules bound to all PNTs polymers due to their molecular recognition interaction involving histidines and Cu(2+)-trisNTA pockets, but with a binding ability that was highly modulated by the average distance between the trisNTA binding sites. Small molecular mass molecules (His6) exhibit a high binding ability to all PNTs polymers, whereas his-tagged proteins bind to PNTs efficiently only when the average distance between trisNTA binding sites is larger than the protein dimensions.

Amperometric detection of lactose using β-galactosidase immobilized in layer-by-layer films.

A direct, low-cost method to determine the concentration of lactose is an important goal with possible impact in various types of industry. In this study, a biosensor is reported that exploits the specific interaction between lactose and the enzyme β-galactosidase (β-Gal) normally employed to process lactose into glucose and galactose for lactose-intolerant people. The biosensor was made with β-Gal immobilized in layer-by-layer (LbL) films with the polyelectrolyte poly(ethylene imine) (PEI) and poly(vinyl sufonate) (PVS) on an indium tin oxide (ITO) electrode modified with a layer of Prussian Blue (PB). With an ITO/PB/(PEI/PVS)1(PEI/β-Gal)30 architecture, lactose could be determined with an amperometric method with sensitivity of 0.31 μA mmol(-1) cm(-2) and detection limit of 1.13 mmol L(-1), which is sufficient for detecting lactose in milk and for clinical exams. Detection occurred via a cascade reaction involving glucose oxidase titrated as electrolytic solution in the electrochemical cell, while PB allowed for operation at 0.0 V versus saturated calomel electrode, thus avoiding effects from interfering species. Sum-frequency generation spectroscopy data for the interface between the LbL film and a buffer containing lactose indicated that β-Gal lost order, which is the first demonstration of structural effects induced by the molecular recognition interaction with lactose.

Shape-based virtual screening, docking, and molecular dynamics simulations to identify Mtb-ASADH inhibitors

Aspartate β-semialdehyde dehydrogenase (ASADH) is a key enzyme for the biosynthesis of essential amino acids and several important metabolites in microbes. Inhibition of ASADH enzyme is a promising drug target strategy against Mycobacterium tuberculosis (Mtb). In this work, in silico approach was used to identify potent inhibitors of Mtb-ASADH. Aspartyl β-difluorophosphonate (β-AFP), a known lead compound, was used to understand the molecular recognition interactions (using molecular docking and molecular dynamics analysis). This analysis helped in validating the computational protocol and established the participation of Arg99, Glu224, Cys130, Arg249, and His256 amino acids as the key amino acids in stabilizing ligand–enzyme interactions for effective binding, an essential feature is H-bonding interactions with the two arginyl residues at the two ends of the ligand. Best binding conformation of β-AFP was selected as a template for shape-based virtual screening (ZINC and NCI databases) to identify compounds that competitively inhibit the Mtb-ASADH. The top rank hits were further subjected to ADME and toxicity filters. Final filter was based on molecular docking analysis. Each screened molecule carries the characteristics of the highly electronegative groups on both sides separated by an average distance of 6 Å. Finally, the best predicted 20 compounds exhibited minimum three H-bonding interactions with Arg99 and Arg249. These identified hits can be further used for designing the more potent inhibitors against ASADH family. MD simulations were also performed on two selected compounds (NSC4862 and ZINC02534243) for further validation. During the MD simulations, both compounds showed same H-bonding interactions and remained bound to key active residues of Mtb-ASADH.