scholarly journals Biological Inspirations: Iron Complexes Mimicking the Catechol Dioxygenases

Materials ◽  
2021 ◽  
Vol 14 (12) ◽  
pp. 3250
Author(s):  
Karolina Kałduńska ◽  
Anna Kozakiewicz ◽  
Magdalena Wujak ◽  
Andrzej Wojtczak
Keyword(s):  
Electrostatic Interactions ◽  
Binding Mode ◽  
Lewis Acidity ◽  
Geometric Isomers ◽  
Micellar Media ◽  
Electronic Effects ◽  
Aromatic Rings ◽  
Catechol Dioxygenase ◽  
Biomimetic Complexes ◽  
Fe Complexes

Within the broad group of Fe non-heme oxidases, our attention was focused on the catechol 1,2- and 2,3-dioxygenases, which catalyze the oxidative cleavage of aromatic rings. A large group of Fe complexes with N/O ligands, ranging from N3 to N2O2S, was developed to mimic the activity of these enzymes. The Fe complexes discussed in this work can mimic the intradiol/extradiol catechol dioxygenase reaction mechanism. Electronic effects of the substituents in the ligand affect the Lewis acidity of the Fe center, increasing the ability to activate dioxygen and enhancing the catalytic activity of the discussed biomimetic complexes. The ligand architecture, the geometric isomers of the complexes, and the substituent steric effects significantly affect the ability to bind the substrate in a monodentate and bidentate manner. The substrate binding mode determines the preferred mechanism and, consequently, the main conversion products. The preferred mechanism of action can also be affected by the solvents and their ability to form the stable complexes with the Fe center. The electrostatic interactions of micellar media, similar to SDS, also control the intradiol/extradiol mechanisms of the catechol conversion by discussed biomimetics.

scholarly journals Novel Trimethine Cyanine Dye as Potential Amyloid Marker

2018 ◽  
Keyword(s):  
Absorption Spectra ◽  
Electrostatic Interactions ◽  
Amyloid Fibrils ◽  
Binding Mode ◽  
Docking Studies ◽  
Cyanine Dye ◽  
Dye Absorption ◽  
Self Association ◽  
A Chain ◽  
Log Normal

The applicability of the novel cyanine dye AK 3-1 to the detection and characterization of pathogenic protein aggregates, amyloid fibrils, was tested using the absorption spectroscopy technique. In an organic solvent dimethyl sulfoxide (DMSO), absorption spectra of AK3-1 exhibits vibrational structure with the relative intensity of 0-0 sub-band being higher than that for the 0-1 sub-band. In an aqueous phase the dye absorption band undergoes hypsochromic shift relative to DMSO due to H-aggregation of the dye. The interaction of AK3-1 with the native and fibrillar insulin was followed by the decrease of monomer band and the enhancement of H-dimer band. To evaluate the relative contributions of the monomeric and aggregated forms, the absorption spectra of the protein-bound dye were deconvoluted using the asymmetric log-normal (LN) function. The analysis of the set of fitting parameters provides evidence for the protein-induced AK3-1 self-association into the head-to-head dimers, with the magnitude of this effect being much more pronounced for fibrillar protein form. The molecular docking studies showed that the AK3-1 monomer tends to associate with the specific arrangement of side chains in the β-sheet formed by L17 leucine residues (of the insulin B-chain), located on the dry steric zipper interface of the fibril, while the dye dimers form stable complexes with the amyloid groove formed by the residues Q15 and E17 of the A-chain, and located on the wet interface of the fibril. The latter binding site is more easily accessible and is additionally stabilized by the electrostatic interactions between the positively charged dye and the E17 residue. This binding mode seems to be prevailing over that for the AK3-1 monomers. Based on the results obtained, AK3-1 may be recommended as a prospective amyloid marker complementary to the classical amyloid reporters Thioflavin T and Congo Red.

scholarly journals A Complete Assessment of Dopamine Receptor-Ligand Interactions through Computational Methods

2019 ◽  
Author(s):  
Beatriz Bueschbell ◽  
Carlos A.V. Barreto ◽  
Antonio J. Preto ◽  
Anke C. Schiedel ◽  
Irina S. Moreira
Keyword(s):  
Dopamine Receptor ◽  
Electrostatic Interactions ◽  
Specific Binding ◽  
Binding Pocket ◽  
Binding Mode ◽  
Receptor Subtypes ◽  
Receptor Ligand ◽  
Pi Stacking ◽  
Ligand Interactions ◽  
New Treatments

Background: Selectively targeting dopamine receptors has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases evolving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elucidated. Methods: Homology modeling and molecular dynamics were applied to construct robust conformational models of all dopamine receptor subtypes (D1-like and D2-like receptors). Fifteen structurally diverse ligands were docked to these models. Contacts at the binding pocket were fully described in order to reveal new structural findings responsible for DR sub-type specificity. Results: We showed that the number of conformations for a receptor:ligand complex was associated to unspecific interactions > 2.5 Å and hydrophobic contacts, while the decoys binding energy was influenced by specific electrostatic interactions. Known residues such as 3.32Asp, the serine microdomain and the aromatic microdomain were found interacting in a variety of modes (HB, SB, π-stacking). Purposed TM2-TM3-TM7 microdomain was found to form a hydrophobic network involving Orthosteric Binding Pocket (OBP) and Secondary Binding Pocket (SBP). T-stacking interactions revealed as especially relevant for some large ligands such as apomorphine, risperidone or aripiprazole. Conclusions: This in silico approach was successful in showing known receptor-ligand interactions as well as in determining unique combinations of interactions, key for the design of more specific ligands.

scholarly journals Ab-initio binding of barnase–barstar with DelPhiForce steered Molecular Dynamics (DFMD) approach

2020 ◽  
Vol 19 (04) ◽  
pp. 2050016
Author(s):  
Mahesh Koirala ◽  
Emil Alexov
Keyword(s):  
Molecular Dynamics ◽  
Electrostatic Interactions ◽  
3D Structure ◽  
Binding Mode ◽  
Steered Molecular Dynamics ◽  
Biological Processes ◽  
Close Proximity ◽  
Ligand Interactions ◽  
Pulling Force

Receptor–ligand interactions are involved in various biological processes, therefore understanding the binding mechanism and ability to predict the binding mode are essential for many biological investigations. While many computational methods exist to predict the 3D structure of the corresponding complex provided the knowledge of the monomers, here we use the newly developed DelPhiForce steered Molecular Dynamics (DFMD) approach to model the binding of barstar to barnase to demonstrate that first-principles methods are also capable of modeling the binding. Essential component of DFMD approach is enhancing the role of long-range electrostatic interactions to provide guiding force of the monomers toward their correct binding orientation and position. Thus, it is demonstrated that the DFMD can successfully dock barstar to barnase even if the initial positions and orientations of both are completely different from the correct ones. Thus, the electrostatics provides orientational guidance along with pulling force to deliver the ligand in close proximity to the receptor.

scholarly journals Insights into G-quadruplex specific recognition by the DEAH-box helicase RHAU: Solution structure of a peptide–quadruplex complex

2015 ◽  
Vol 112 (31) ◽  
pp. 9608-9613 ◽  
Author(s):  
Brahim Heddi ◽  
Vee Vee Cheong ◽  
Herry Martadinata ◽  
Anh Tuân Phan
Keyword(s):  
Electrostatic Interactions ◽  
Solution Structure ◽  
Binding Mode ◽  
Structural Basis ◽  
Cellular Processes ◽  
Charged Amino Acids ◽  
G Quadruplex ◽  
Guanine Base ◽  
Nucleic Acid Structures ◽  
Phosphate Groups

Four-stranded nucleic acid structures called G-quadruplexes have been associated with important cellular processes, which should require G-quadruplex–protein interaction. However, the structural basis for specific G-quadruplex recognition by proteins has not been understood. The DEAH (Asp-Glu-Ala-His) box RNA helicase associated with AU-rich element (RHAU) (also named DHX36 or G4R1) specifically binds to and resolves parallel-stranded G-quadruplexes. Here we identified an 18-amino acid G-quadruplex-binding domain of RHAU and determined the structure of this peptide bound to a parallel DNA G-quadruplex. Our structure explains how RHAU specifically recognizes parallel G-quadruplexes. The peptide covers a terminal guanine base tetrad (G-tetrad), and clamps the G-quadruplex using three-anchor-point electrostatic interactions between three positively charged amino acids and negatively charged phosphate groups. This binding mode is strikingly similar to that of most ligands selected for specific G-quadruplex targeting. Binding to an exposed G-tetrad represents a simple and efficient way to specifically target G-quadruplex structures.

scholarly journals Structural dynamics and catalytic mechanism of ATP13A2 (PARK9) from simulations

2021 ◽  
Author(s):  
Teodora Mateeva ◽  
Marco Klaehn ◽  
Edina Rosta
Keyword(s):  
Barrier Height ◽  
Catalytic Reaction ◽  
Active Site ◽  
Electrostatic Interactions ◽  
Catalytic Mechanism ◽  
Atp Hydrolysis ◽  
Binding Mode ◽  
Full Length ◽  
Dimensional Structure ◽  
Missense Mutations

ATP13A2 is a gene encoding a protein of the P5B subfamily of ATPases and is a PARK gene. Molecular defects of the gene are mainly associated with variations of Parkinson's disease (PD). Despite the established importance of the protein in regulating neuronal integrity, the three-dimensional structure of the protein currently remains unresolved crystallographically. We have modelled the structure and reactivity of the full-length protein in its E1-ATP state. Using Molecular Dynamics (MD), Quantum cluster and Quantum Mechanical/Molecular mechanical (QM/MM) methods, we aimed at describing the main catalytic reaction, leading to the phosphorylation of Asp513. Our MD simulations suggest that two positively charged Mg2+ cations are present at the active site during the catalytic reaction, stabilizing a specific triphosphate binding mode. Using QM/MM calculations, we subsequently calculated the reaction profiles for the phosphate transfer step in the presence of one and two Mg2+ cations. The calculated barrier heights in both cases are found to be around 10.5 and 13.0 kcal mol-1, respectively. We elucidated details of the catalytically competent ATP conformation and the binding mode of the second Mg2+ cofactor. We also examined the role of the conserved Arg686 and Lys859 catalytic residues. We observed that by lowering significantly the barrier height of the ATP hydrolysis reaction, Arg686 had significant effect on the reaction. The removal of Arg686 increased the barrier height for the ATP hydrolysis by ~3.5 kcal mol-1 while the removal of key electrostatic interactions created by Lys859 to the gamma-phosphate and Arg513 destabilizes the reactant state. When missense mutations occur in close proximity to an active site residue, they can interfere with the barrier height of the reaction, which can halt the normal enzymatic rate of the protein. We also identified the main binding pockets in the full-length structure, including the pocket in the transmembrane region, which is likely where ATP13A2 cargo binds.

scholarly journals On the Different Mode of Action of Au(I)/Ag(I)-NHC Bis-Anthracenyl Complexes Towards Selected Target Biomolecules

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5446
Author(s):  
Francesca Binacchi ◽  
Federica Guarra ◽  
Damiano Cirri ◽  
Tiziano Marzo ◽  
Alessandro Pratesi ◽  
...  
Keyword(s):  
Electrostatic Interactions ◽  
Silver Chloride ◽  
Binding Mode ◽  
Heterocyclic Carbenes ◽  
Groove Binding ◽  
Double Stranded Dna ◽  
G Quadruplex ◽  
Gold Compounds ◽  
Geometrical Constraints ◽  
Fluorescence Titrations

Gold and silver N-heterocyclic carbenes (NHCs) are emerging for therapeutic applications. Multiple techniques are here used to unveil the mechanistic details of the binding to different biosubstrates of bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) silver chloride [Ag(EIA)2]Cl and bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) gold chloride [Au(EIA)2]Cl. As the biosubstrates, we tested natural double-stranded DNA, synthetic RNA polynucleotides (single-poly(A), double-poly(A)poly(U) and triple-stranded poly(A)2poly(U)), DNA G-quadruplex structures (G4s), and bovine serum albumin (BSA) protein. Absorbance and fluorescence titrations, mass spectrometry together with melting and viscometry tests show significant differences in the binding features between silver and gold compounds. [Au(EIA)2]Cl covalently binds BSA. It is here evidenced that the selectivity is high: low affinity and external binding for all polynucleotides and G4s are found. Conversely, in the case of [Ag(EIA)2]Cl, the binding to BSA is weak and relies on electrostatic interactions. [Ag(EIA)2]Cl strongly/selectively interacts only with double strands by a mechanism where intercalation plays the major role, but groove binding is also operative. The absence of an interaction with triplexes indicates the major role played by the geometrical constraints to drive the binding mode.

Study of the Interaction of Ciprofloxacin and Sparfloxacin with Biomolecules by Spectral, Electrochemical and Molecular Docking Methods

2018 ◽  
Vol 78 ◽  
pp. 1-29 ◽  
Author(s):  
N. Rajendiran ◽  
M. Suresh
Keyword(s):  
Cyclic Voltammetry ◽  
Molecular Docking ◽  
Binding Sites ◽  
Electrostatic Interactions ◽  
Fluorescence Spectra ◽  
Blue Shift ◽  
Binding Mode ◽  
Interaction Processes ◽  
Good Accordance ◽  
Uv Visible

Interactions of ciprofloxacin and sparfloxacin with different biomolecules (DNA, RNA and BSA) are investigated by UV–Visible spectroscopy, fluorescence spectroscopy, cyclic voltammetry and molecular docking methods. Upon increasing the concentration of the biomolecules, the absorption maxima of ciprofloxacin and sparfloxacin are red shifted in the aqueous solutions whereas red or blue shift noticed in the fluorescence spectra. The negative free energy changes suggest that the interaction processes are spontaneous. Cyclic voltammetry results suggested that when the drug concentration is increased, the anodic electrode potential increased. Molecular docking results showed that hydrophobic forces, electrostatic interactions, and hydrogen bonds played vital roles in the interaction drugs with biomolecules. The molecular docking calculation clarifies the binding mode and the binding sites are in good accordance with the experiment results.

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