The binding modes of VIVO2+ ions in blood proteins and enzymes

2020 ◽  
Vol 56 (81) ◽  
pp. 12218-12221 ◽  
Author(s):  
Giuseppe Sciortino ◽  
Eugenio Garribba
Keyword(s):  
Binding Sites ◽  
Binding Modes ◽  
Blood Proteins ◽  
Combined Approach ◽  
Spectroscopic Behaviour

Herein, we report a combined approach of full DFT and MM techniques to unveil the binding sites and modes of VIVO2+ ions with important blood proteins and enzymes and to explain their spectroscopic behaviour.

Reversibly Sampling Conformations and Binding Modes Using Molecular Darting

2020 ◽  
Author(s):  
Samuel C. Gill ◽  
David Mobley
Keyword(s):  
Monte Carlo ◽  
Ligand Binding ◽  
Binding Sites ◽  
Degrees Of Freedom ◽  
Dynamics Simulation ◽  
Hiv Integrase ◽  
Binding Modes ◽  
System A ◽  
Multiple Binding ◽  
Internal Degrees Of Freedom

<div>Sampling multiple binding modes of a ligand in a single molecular dynamics simulation is difficult. A given ligand may have many internal degrees of freedom, along with many different ways it might orient itself a binding site or across several binding sites, all of which might be separated by large energy barriers. We have developed a novel Monte Carlo move called Molecular Darting (MolDarting) to reversibly sample between predefined binding modes of a ligand. Here, we couple this with nonequilibrium candidate Monte Carlo (NCMC) to improve acceptance of moves.</div><div>We apply this technique to a simple dipeptide system, a ligand binding to T4 Lysozyme L99A, and ligand binding to HIV integrase in order to test this new method. We observe significant increases in acceptance compared to uniformly sampling the internal, and rotational/translational degrees of freedom in these systems.</div>

Inhibitor Binding Sites in the Protein Tyrosine Phosphatase SHP-2

2020 ◽  
Vol 20 (11) ◽  
pp. 1017-1030
Author(s):  
Haonan Zhang ◽  
Zhengquan Gao ◽  
Chunxiao Meng ◽  
Xiangqian Li ◽  
Dayong Shi
Keyword(s):  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Binding Sites ◽  
Drug Target ◽  
Tyrosine Phosphatase ◽  
Cancer Drug ◽  
Cellular Activity ◽  
Binding Modes ◽  
Inhibitor Binding ◽  
Protein Tyrosine

Protein tyrosine phosphatase 2 (SHP-2) has long been proposed as a cancer drug target. Several small-molecule compounds with different mechanisms of SHP-2 inhibition have been reported, but none are commercially available. Pool selectivity over protein tyrosine phosphatase 1 (SHP-1) and a lack of cellular activity have hindered the development of selective SHP-2 inhibitors. In this review, we describe the binding modes of existing inhibitors and SHP-2 binding sites, summarize the characteristics of the sites involved in selectivity, and identify the suitable groups for interaction with the binding sites.

scholarly journals Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607

2021 ◽  
Vol 141 (5) ◽  
pp. 697-708
Author(s):  
Yang Shi ◽  
Alexey G. Murzin ◽  
Benjamin Falcon ◽  
Alexander Epstein ◽  
Jonathan Machin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Binding Sites ◽  
Binding Activity ◽  
Cortical Atrophy ◽  
Binding Modes ◽  
Major Site ◽  
Age Related ◽  
Positron Emission

AbstractTau and Aβ assemblies of Alzheimer’s disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.

scholarly journals Drug interaction with radiopharmaceuticals: effect on the labeling of red blood cells with technetium-99m and on the bioavailability of radiopharmaceuticals

2002 ◽  
Vol 45 (spe) ◽  
pp. 143-149 ◽  
Author(s):  
Maria Luisa Gomes ◽  
Marcia B. Nunes de Oliveira ◽  
Mario Bernardo-Filho
Keyword(s):  
Drug Interaction ◽  
Binding Sites ◽  
Correct Diagnosis ◽  
Blood Proteins ◽  
Direct Oxidation ◽  
Direct Inhibition ◽  
Technetium 99M ◽  
Synthetic Drugs ◽  
Stannous Ion ◽  
Blood Elements

The evidence that natural and synthetic drugs can affect radiolabeling or bioavailability of radiopharmaceuticals in setting of nuclear medicine clinic is already known. However, this drug interaction with radiopharmaceuticals (DIR) is not completely understood. Several authors have described the effect of drugs on the labeling of blood elements with technetium-99m (99mTc) and on the biodistribution of radiopharmaceuticals. When the DIR is known, if desirable or undesirable, the natural consequence is a correct diagnosis. However, when it is unknown, it is undesirable and the consequences are the possibility of misdiagnosis and/or the repetition of the examination with an increase of radiation dose to the patient. The possible explanation to the appearance of DIR are (a) radiopharmaceutical modification, (b) alteration of the labeling efficiency of the radiopharmaceutical, (c) modification of the target, (d) modification of no target and/or the (e) alteration of the binding of the radiopharmaceutical on the blood proteins. The effect of drugs on the labeling of blood elements with 99mTc might be explained by (i) a direct inhibition (chelating action) of the stannous and pertechnetate ions, (ii) damage induced in the plasma membrane, (iii) competition of the cited ions for the same binding sites, (iv) possible generation of reactive oxygen species that could oxidize the stannous ion and/or (v) direct oxidation of the stannous ion. In conclusion, the development of biological models to study the DIR is highly relevant.

scholarly journals A network of phosphatidylinositol 4,5-bisphosphate binding sites regulates gating of the Ca2+-activated Cl− channel ANO1 (TMEM16A)

2019 ◽  
Vol 116 (40) ◽  
pp. 19952-19962 ◽  
Author(s):  
Kuai Yu ◽  
Tao Jiang ◽  
YuanYuan Cui ◽  
Emad Tajkhorshid ◽  
H. Criss Hartzell
Keyword(s):  
Protein Interactions ◽  
Binding Sites ◽  
Neuronal Excitability ◽  
Computational Study ◽  
Channel Gating ◽  
Md Simulations ◽  
Fluid Secretion ◽  
Hydroxyl Groups ◽  
Binding Modes ◽  
Cytoplasmic Extension

ANO1 (TMEM16A) is a Ca2+-activated Cl− channel that regulates diverse cellular functions including fluid secretion, neuronal excitability, and smooth muscle contraction. ANO1 is activated by elevation of cytosolic Ca2+ and modulated by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Here, we describe a closely concerted experimental and computational study, including electrophysiology, mutagenesis, functional assays, and extended sampling of lipid–protein interactions with molecular dynamics (MD) to characterize PI(4,5)P2 binding modes and sites on ANO1. ANO1 currents in excised inside-out patches activated by 270 nM Ca2+ at +100 mV are increased by exogenous PI(4,5)P2 with an EC50 = 1.24 µM. The effect of PI(4,5)P2 is dependent on membrane voltage and Ca2+ and is explained by a stabilization of the ANO1 Ca2+-bound open state. Unbiased atomistic MD simulations with 1.4 mol% PI(4,5)P2 in a phosphatidylcholine bilayer identified 8 binding sites with significant probability of binding PI(4,5)P2. Three of these sites captured 85% of all ANO1–PI(4,5)P2 interactions. Mutagenesis of basic amino acids near the membrane–cytosol interface found 3 regions of ANO1 critical for PI(4,5)P2 regulation that correspond to the same 3 sites identified by MD. PI(4,5)P2 is stabilized by hydrogen bonding between amino acid side chains and phosphate/hydroxyl groups on PI(4,5)P2. Binding of PI(4,5)P2 alters the position of the cytoplasmic extension of TM6, which plays a crucial role in ANO1 channel gating, and increases the accessibility of the inner vestibule to Cl− ions. We propose a model consisting of a network of 3 PI(4,5)P2 binding sites at the cytoplasmic face of the membrane allosterically regulating ANO1 channel gating.

scholarly journals Molecular Modeling Studies on the Interactions of Aflatoxin B1 and Its Metabolites with Human Acetylcholinesterase. Part II: Interactions with the Catalytic Anionic Site (CAS)

Toxins ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 389 ◽  
Author(s):  
Joyce de Almeida ◽  
Rafael Dolezal ◽  
Ondrej Krejcar ◽  
Kamil Kuca ◽  
Kamil Musilek ◽  
...  
Keyword(s):  
Aflatoxin B1 ◽  
Binding Sites ◽  
Mixed Type ◽  
Experimental Studies ◽  
Common Type ◽  
Binding Modes ◽  
Anionic Site ◽  
Chronic Effects ◽  
Molecular Modeling Studies ◽  
Acute And Chronic Effects

The most common type of aflatoxin (AFT) found in nature is aflatoxin B1 (AFB1). This micotoxin is extremely hepatotoxic and carcinogenic to mammals, with acute and chronic effects. It is believed that this could be related to the capacity of AFB1 and its metabolites in inhibiting the enzyme acetylcholinesterase (AChE). In a previous work, we performed an inedited theoretical investigation on the binding modes of these molecules on the peripheral anionic site (PAS) of human AChE (HssAChE), revealing that the metabolites can also bind in the PAS in the same way as AFB1. Here, we investigated the binding modes of these compounds on the catalytic anionic site (CAS) of HssAChE to compare the affinity of the metabolites for both binding sites as well as verify which is the preferential one. Our results corroborated with experimental studies pointing to AFB1 and its metabolites as mixed-type inhibitors, and pointed to the residues relevant for the stabilization of these compounds on the CAS of HssAChE.

scholarly journals Highly Efficient, Tripodal Ion-Pair Receptors for Switching Selectivity between Acetates and Sulfates Using Solid–Liquid and Liquid–Liquid Extractions

2020 ◽  
Vol 21 (24) ◽  
pp. 9465
Author(s):  
Marta Zaleskaya ◽  
Łukasz Dobrzycki ◽  
Jan Romański
Keyword(s):  
Binding Sites ◽  
Liquid Extraction ◽  
Ion Pair ◽  
Anion Binding ◽  
Binding Modes ◽  
Anion Receptor ◽  
X Ray ◽  
Liquid Liquid Extraction ◽  
Solid Liquid Extraction ◽  
Solid Liquid

A tripodal, squaramide-based ion-pair receptor 1 was synthesized in a modular fashion, and 1H NMR and UV-vis studies revealed its ability to interact more efficiently with anions with the assistance of cations. The reference tripodal anion receptor 2, lacking a crown ether unit, was found to lose the enhancement in anion binding induced by presence of cations. Besides the ability to bind anions in enhanced manner by the “single armed” ion-pair receptor 3, the lack of multiple and prearranged binding sites resulted in its much lower affinity towards anions than in the case of tripodal receptors. Unlike with receptors 2 or 3, the high affinity of 1 towards salts opens up the possibility of extracting extremely hydrophilic sulfate anions from aqueous to organic phase. The disparity in receptor 1 binding modes towards monovalent anions and divalent sulfates assures its selectivity towards sulfates over other lipophilic salts upon liquid–liquid extraction (LLE) and enables the Hofmeister bias to be overcome. By changing the extraction conditions from LLE to SLE (solid–liquid extraction), a switch of selectivity from sulfates to acetates was achieved. X-ray measurements support the ability of anion binding by cooperation of the arms of receptor 1 together with simultaneous binding of cations.

scholarly journals Structural and Biochemical Studies on the Regulation of Biotin Carboxylase by Substrate Inhibition and Dimerization

2011 ◽  
Vol 286 (27) ◽  
pp. 24417-24425 ◽  
Author(s):  
Chi-Yuan Chou ◽  
Liang Tong
Keyword(s):  
Binding Sites ◽  
Analytical Ultracentrifugation ◽  
Substrate Inhibition ◽  
Kinetic Studies ◽  
The Other ◽  
Biotin Carboxylase ◽  
Binding Modes ◽  
Wild Type ◽  
Wild Type Enzyme ◽  
Dimer Interface

Biotin carboxylase (BC) activity is shared among biotin-dependent carboxylases and catalyzes the Mg-ATP-dependent carboxylation of biotin using bicarbonate as the CO2 donor. BC has been studied extensively over the years by structural, kinetic, and mutagenesis analyses. Here we report three new crystal structures of Escherichia coli BC at up to 1.9 Å resolution, complexed with different ligands. Two structures are wild-type BC in complex with two ADP molecules and two Ca2+ ions or two ADP molecules and one Mg2+ ion. One ADP molecule is in the position normally taken by the ATP substrate, whereas the other ADP molecule occupies the binding sites of bicarbonate and biotin. One Ca2+ ion and the Mg2+ ion are associated with the ADP molecule in the active site, and the other Ca2+ ion is coordinated by Glu-87, Glu-288, and Asn-290. Our kinetic studies confirm that ATP shows substrate inhibition and that this inhibition is competitive against bicarbonate. The third structure is on the R16E mutant in complex with bicarbonate and Mg-ADP. Arg-16 is located near the dimer interface. The R16E mutant has only a 2-fold loss in catalytic activity compared with the wild-type enzyme. Analytical ultracentrifugation experiments showed that the mutation significantly destabilized the dimer, although the presence of substrates can induce dimer formation. The binding modes of bicarbonate and Mg-ADP are essentially the same as those to the wild-type enzyme. However, the mutation greatly disrupted the dimer interface and caused a large re-organization of the dimer. The structures of these new complexes have implications for the catalysis by BC.

scholarly journals Deprotonation of resorcinarenes and novel ammonium salt complexes

2014 ◽  
Vol 70 (a1) ◽  
pp. C678-C678
Author(s):  
Ngong Beyeh ◽  
Arto Valkonen ◽  
Fanfang Pan ◽  
Kari Rissanen
Keyword(s):  
Hydrogen Bonds ◽  
Binding Sites ◽  
Molecular Complexes ◽  
Ammonium Salts ◽  
Hydroxyl Groups ◽  
Binding Modes ◽  
Intermolecular Hydrogen Bonds ◽  
Guest Molecules ◽  
Cone Conformation ◽  
Intramolecular Hydrogen

The bowl shape cavity of resorcinarenes usually stabilized by four intramolecular hydrogen bonds offers an interesting array of binding modes such as C–H...π and cation...π interactions to recognize a variety of guests. The multiple hydroxyl groups can participate in a series of intermolecular hydrogen bonds with guest molecules. This unique cone conformation of resorcinarenes has led to the synthesis of many receptors with convergent arrangement of binding sites suitable for molecular recognition in many applications. Unfunctionalized resorcinarenes are known to easily form molecular complexes with guests of varying shapes and sizes. Amines are very common bases used in many catalytic processes. A good example is the use of amines as bases in the alkylation and acylation of resorcinarenes leading to cavitands, carcerands, hemicarcerands and velcrands. The use of amines in such reactions is to deprotonate the resorcinarene hydroxyl groups, hence facilitating the alkylation and acylation processes. The subsequently protonated ammonium cation then forms interesting supramolecular complexes with the anionic and dianionic resorcinarenes. Furthermore, secondary and tertiary ammonium salts possess hydrogen bond donating -NH2 and -NH respectively and these can further enhance their complexation through intermolecular hydrogen bonds. Here we present our recent examples of supramolecular assemblies resulting from the deprotonation of resorcinarenes by mono- and dibasic amines. Also, our latest supramolecular co-crystals between resorcinarenes as the receptors and a series of secondary and tertiary mono- and diammonium cations are illustrated.

scholarly journals Prediction of Binding Sites of Zinc Complex Using Experimental and Computational ModelingApproach

2017 ◽  
Vol 27 (4) ◽  
Author(s):  
Fadhil Lafta ◽  
Faliah Hasen Ali ◽  
Salah Aldin Jassim
Keyword(s):  
Atomic Absorption ◽  
Computational Chemistry ◽  
Binding Sites ◽  
Zinc Complex ◽  
Molar Ratio ◽  
Binding Modes ◽  
Hartree Fock ◽  
Coordination Sites ◽  
Homo Lumo

The binding modes of a new zinc complex derived from 3-(5-bromo-2-hydroxybenzylideneamino)-2-(5-bromo-2-hydroxyphenyl)-2,3-dihydroquinazoline-4(1H)-one withdivalent zinc was studied using both experimental and computational chemistry. 1H NMR, IR, molar ratio and atomic absorption were used to predict the characterization of zinc complex. Hartree–Fock (HF) method  was selected to determine the HOMO-LUMO gap of several possibilities of binding sites to describe the more stable structure which reflects the more possible coordination sites of ligand to Zn+2 ion. Good matching between theoretical and experimental results was found which concluded the tetra dentate behavior of the ligand.

Sign in / Sign up

Export Citation Format

Share Document