DNA Photocleavage and Binding Modes of Methylene Violet 3RAX and its Derivatives: Effect of Functional Groups

2017 ◽  
Vol 70 (7) ◽  
pp. 830 ◽  
Author(s):  
Ke Yang ◽  
Xiong Zhang ◽  
Fang Yang ◽  
Fengshou Wu ◽  
Xiulan Zhang ◽  
...  
Keyword(s):  
Singlet Oxygen ◽  
Electrostatic Interactions ◽  
1H Nmr Spectroscopy ◽  
Binding Mode ◽  
Binding Modes ◽  
Oxygen Production ◽  
Groove Binding ◽  
Dna Photocleavage ◽  
Intercalative Mode ◽  
Methylene Violet

With 4′-amino-N,N-diethylaniline and aniline as starting materials, methylene violet 3RAX 1 and its derivatives 2–5 were synthesised. The five compounds were characterised by IR, UV-vis, and 1H NMR spectroscopy and mass spectrometry. The binding mode between the synthesised compounds and DNA were investigated. The results show that both compounds 1 and 5 bind to DNA by an intercalative mode, while compounds 2–4 interact with DNA through a mixed binding mode involving groove binding and electrostatic interactions. The photocleavage ability of the five compounds to DNA were calculated to be 38, 40, 30, 20, and 13 %, respectively, when their concentration was adjusted to 400 μM. The singlet oxygen production of compounds measured by the 1,3-diphenylisobenzofuran method was consistent with the trend of DNA photocleavage ability. The DNA studies suggest that the binding mode between methylene violet 3RAX and DNA, the ability of methylene violet 3RAX to generate singlet oxygen, and the DNA photocleavage activity could be adjusted through modification of the amino group on methylene violet 3RAX.

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.

scholarly journals Theoretical Study of Sequence Selectivity and Preferred Binding Mode of Psoralen with DNA

2007 ◽  
Vol 2007 ◽  
pp. 1-5 ◽  
Author(s):  
Patricia Saenz-Méndez ◽  
Rita C. Guedes ◽  
Daniel J. V. A. dos Santos ◽  
Leif A. Eriksson
Keyword(s):  
Molecular Dynamics ◽  
Theoretical Study ◽  
Binding Mode ◽  
Minor Groove Binding ◽  
Binding Modes ◽  
Groove Binding ◽  
Base Pairs ◽  
Sequence Selectivity ◽  
Molecular Dynamics Methods ◽  
Low Efficiency

Psoralen interaction with two models of DNA was investigated using molecular mechanics and molecular dynamics methods. Calculated energies of minor groove binding and intercalation were compared in order to define a preferred binding mode for the ligand. We found that both binding modes are possible, explaining the low efficiency for monoadduct formation from intercalated ligands. A comparison between the interaction energy for intercalation between different base pairs suggests that the observed sequence selectivity is due to favorable intercalation in 5′-TpA in (AT)n sequences.

scholarly journals The Roles of Electrostatic Interactions in Capsid Assembly Mechanisms of Giant Viruses

2019 ◽  
Vol 20 (8) ◽  
pp. 1876 ◽  
Author(s):  
Yuejiao Xian ◽  
Chitra B. Karki ◽  
Sebastian Miki Silva ◽  
Lin Li ◽  
Chuan Xiao
Keyword(s):  
Self Assembly ◽  
Electrostatic Interactions ◽  
Virus Assembly ◽  
Binding Mode ◽  
Giant Virus ◽  
Capsid Assembly ◽  
Fold Axis ◽  
Binding Modes ◽  
Dna Viruses ◽  
Giant Viruses

In the last three decades, many giant DNA viruses have been discovered. Giant viruses present a unique and essential research frontier for studies of self-assembly and regulation of supramolecular assemblies. The question on how these giant DNA viruses assemble thousands of proteins so accurately to form their protein shells, the capsids, remains largely unanswered. Revealing the mechanisms of giant virus assembly will help to discover the mysteries of many self-assembly biology problems. Paramecium bursaria Chlorella virus-1 (PBCV-1) is one of the most intensively studied giant viruses. Here, we implemented a multi-scale approach to investigate the interactions among PBCV-1 capsid building units called capsomers. Three binding modes with different strengths are found between capsomers around the relatively flat area of the virion surface at the icosahedral 2-fold axis. Furthermore, a capsomer structure manipulation package is developed to simulate the capsid assembly process. Using these tools, binding forces among capsomers were investigated and binding funnels were observed that were consistent with the final assembled capsid. In addition, total binding free energies of each binding mode were calculated. The results helped to explain previous experimental observations. Results and tools generated in this work established an initial computational approach to answer current unresolved questions regarding giant virus assembly mechanisms. Results will pave the way for studying more complicated process in other biomolecular structures.

Synthesis, singlet oxygen generation and DNA photocleavage of β,β′-conjugated polycationic porphyrins

2019 ◽  
Vol 23 (06) ◽  
pp. 655-663 ◽  
Author(s):  
Li Chen ◽  
Yimei Zhao ◽  
Xinyu Sun ◽  
Jun Jiang ◽  
Fengshou Wu ◽  
...  
Keyword(s):  
Singlet Oxygen ◽  
Fluorescence Emission ◽  
Binding Constants ◽  
Binding Mode ◽  
Binding Modes ◽  
Cleavage Rate ◽  
Oxygen Generation ◽  
Vis Spectroscopy ◽  
Pbr322 Plasmid ◽  
Ct Dna

In this paper, three [Formula: see text],[Formula: see text]-conjugated cationic porphyrin compounds were designed and synthesized. The structure of the intermediates and desired porphyrins were confirmed by UV, IR, 1H NMR, MS and elemental analysis. The interaction modes between these porphyrins and ct-DNA were studied by UV-vis spectroscopy and fluorescence emission spectroscopy. The results showed that PCP 1 had an external binding mode with DNA at low DNA concentration and could intercalate DNA with the increase of concentration. PCP 2 interacted with DNA through an external binding mode, and PCP 3 could insert into DNA. The binding constants ([Formula: see text] between PCP1[Formula: see text]PCP3 and ct-DNA were calculated to be 8.41 × 104, 7.33 × 104 and 4.14 × 104 M[Formula: see text], respectively. The singlet oxygen (1O[Formula: see text] generation of PCP1[Formula: see text]PCP3 was determined by the 1,3-diphenylisobenzofuran (DPBF) method using tetrapyridylporphyrin (H2TMPyP) as a reference. The 1O2 generation rate of PCP1[Formula: see text]PCP3 followed the order of PCP2 >PCP1>H2TMPyP >PCP3. Subsequently, the photocleavage effect of porphyrins on pBR322 plasmid DNA was studied by gel electrophoresis. At 10.0 [Formula: see text]M, PCP1 and PCP2 could cleave DNA completely. At 2.0 [Formula: see text]M, the cleavage rate of DNA by PCP3 was 57.5%, which was significantly higher than that of H2TMPyP (38.8%). These results verified that the amount of cationic ions in the porphyrin structure could affect the binding modes of porphyrins with DNA and their cleavage ability of DNA.

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes Using Nonequilibrium Candidate Monte Carlo

2017 ◽  
Author(s):  
Samuel Gill ◽  
Nathan M. Lim ◽  
Patrick Grinaway ◽  
Ariën S. Rustenburg ◽  
Josh Fass ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Ligand Binding ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
Enhanced Sampling ◽  
Recent Success ◽  
Multiple Binding ◽  
Proper Sampling

<div>Accurately predicting protein-ligand binding is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation timescales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes.</div><div><br></div><div>In this technique the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over two orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step towards applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding Modes of Ligands using Enhanced Sampling (BLUES) package which is freely available on GitHub.</div>

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes Using Nonequilibrium Candidate Monte Carlo

2018 ◽  
Author(s):  
Samuel Gill ◽  
Nathan M. Lim ◽  
Patrick Grinaway ◽  
Ariën S. Rustenburg ◽  
Josh Fass ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Ligand Binding ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
Enhanced Sampling ◽  
Recent Success ◽  
Multiple Binding ◽  
Proper Sampling

<div>Accurately predicting protein-ligand binding is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation timescales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes.</div><div><br></div><div>In this technique the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over two orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step towards applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding Modes of Ligands using Enhanced Sampling (BLUES) package which is freely available on GitHub.</div>

scholarly journals Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 686 ◽  
Author(s):  
Alexander Neumann ◽  
Viktor Engel ◽  
Andhika B. Mahardhika ◽  
Clara T. Schoeder ◽  
Vigneshwaran Namasivayam ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
G Protein ◽  
Phenyl Ring ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Binding Modes ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist ∆9-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still require unambiguous confirmation. In the present study, we constructed a homology model of the human GPR18 based on an ensemble of three GPCR crystal structures to investigate the binding modes of the agonist THC and the recently reported antagonists which feature an imidazothiazinone core to which a (substituted) phenyl ring is connected via a lipophilic linker. Docking and molecular dynamics simulation studies were performed. As a result, a hydrophobic binding pocket is predicted to accommodate the imidazothiazinone core, while the terminal phenyl ring projects towards an aromatic pocket. Hydrophobic interaction of Cys251 with substituents on the phenyl ring could explain the high potency of the most potent derivatives. Molecular dynamics simulation studies suggest that the binding of imidazothiazinone antagonists stabilizes transmembrane regions TM1, TM6 and TM7 of the receptor through a salt bridge between Asp118 and Lys133. The agonist THC is presumed to bind differently to GPR18 than to the distantly related CB receptors. This study provides insights into the binding mode of GPR18 agonists and antagonists which will facilitate future drug design for this promising potential drug target.

scholarly journals Functionalization of Photosensitized Silica Nanoparticles for Advanced Photodynamic Therapy of Cancer

2021 ◽  
Vol 22 (12) ◽  
pp. 6618
Author(s):  
Ruth Prieto-Montero ◽  
Alejandro Prieto-Castañeda ◽  
Alberto Katsumiti ◽  
Miren P. Cajaraville ◽  
Antonia R. Agarrabeitia ◽  
...  
Keyword(s):  
Singlet Oxygen ◽  
Silica Nanoparticles ◽  
Mesoporous Silica Nanoparticles ◽  
Absorption Capacity ◽  
Oxygen Production ◽  
Photodynamic Therapy Of Cancer ◽  
Custom Made ◽  
Fluorescence Efficiency ◽  
Covalently Linked

BODIPY dyes have recently attracted attention as potential photosensitizers. In this work, commercial and novel photosensitizers (PSs) based on BODIPY chromophores (haloBODIPYs and orthogonal dimers strategically designed with intense bands in the blue, green or red region of the visible spectra and high singlet oxygen production) were covalently linked to mesoporous silica nanoparticles (MSNs) further functionalized with PEG and folic acid (FA). MSNs approximately 50 nm in size with different functional groups were synthesized to allow multiple alternatives of PS-PEG-FA decoration of their external surface. Different combinations varying the type of PS (commercial Rose Bengal, Thionine and Chlorine e6 or custom-made BODIPY-based), the linkage design, and the length of PEG are detailed. All the nanosystems were physicochemically characterized (morphology, diameter, size distribution and PS loaded amount) and photophysically studied (absorption capacity, fluorescence efficiency, and singlet oxygen production) in suspension. For the most promising PS-PEG-FA silica nanoplatforms, the biocompatibility in dark conditions and the phototoxicity under suitable irradiation wavelengths (blue, green, or red) at regulated light doses (10–15 J/cm2) were compared with PSs free in solution in HeLa cells in vitro.

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