scholarly journals The Interaction of Cyclic Naphthalene Diimide with G-Quadruplex under Molecular Crowding Condition

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 668 ◽  
Author(s):  
Tingting Zou ◽  
Shinobu Sato ◽  
Rui Yasukawa ◽  
Ryusuke Takeuchi ◽  
Shunsuke Ozaki ◽  
...  
Keyword(s):  
Titration Calorimetry ◽  
Binding Affinities ◽  
Molecular Crowding ◽  
Biological Regulation ◽  
Specific Targeting ◽  
Absorbance Spectroscopy ◽  
Naphthalene Diimide ◽  
Telomere Sequence ◽  
G Quadruplex ◽  
Cellular Condition

G-quadruplex specific targeting molecules, also termed as G4 ligands, are attracting increasing attention for their ability to recognize and stabilize G-quadruplex and high potentiality for biological regulation. However, G4 ligands recognizing G-quadruplex were generally investigated within a dilute condition, which might be interfered with under a cellular crowding environment. Here, we designed and synthesized several new cyclic naphthalene diimide (cNDI) derivatives, and investigated their interaction with G-quadruplex under molecular crowding condition (40% v/v polyethylene glycol (PEG)200) to mimic the cellular condition. The results indicated that, under molecular crowding conditions, cNDI derivatives were still able to recognize and stabilize G-quadruplex structures based on circular dichroism measurement. The binding affinities were slightly decreased but still comparatively high upon determination by isothermal titration calorimetry and UV-vis absorbance spectroscopy. More interestingly, cNDI derivatives were observed with preference to induce a telomere sequence to form a hybrid G-quadruplex under cation-deficient molecular crowding conditions.

scholarly journals Overlapping but distinct: a new model for G-quadruplex biochemical specificity

2021 ◽  
Author(s):  
Martin Volek ◽  
Sofia Kolesnikova ◽  
Katerina Svehlova ◽  
Pavel Srb ◽  
Ráchel Sgallová ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Drug Design ◽  
Solution Structure ◽  
Biochemical Data ◽  
Biological Regulation ◽  
New Model ◽  
G Quadruplex ◽  
Range Of Functions ◽  
Nucleic Acid Structures ◽  
Sequence Requirements

Abstract G-quadruplexes are noncanonical nucleic acid structures formed by stacked guanine tetrads. They are capable of a range of functions and thought to play widespread biological roles. This diversity raises an important question: what determines the biochemical specificity of G-quadruplex structures? The answer is particularly important from the perspective of biological regulation because genomes can contain hundreds of thousands of G-quadruplexes with a range of functions. Here we analyze the specificity of each sequence in a 496-member library of variants of a reference G-quadruplex with respect to five functions. Our analysis shows that the sequence requirements of G-quadruplexes with these functions are different from one another, with some mutations altering biochemical specificity by orders of magnitude. Mutations in tetrads have larger effects than mutations in loops, and changes in specificity are correlated with changes in multimeric state. To complement our biochemical data we determined the solution structure of a monomeric G-quadruplex from the library. The stacked and accessible tetrads rationalize why monomers tend to promote a model peroxidase reaction and generate fluorescence. Our experiments support a model in which the sequence requirements of G-quadruplexes with different functions are overlapping but distinct. This has implications for biological regulation, bioinformatics, and drug design.

scholarly journals G-Quadruplexes and Their Ligands: Biophysical Methods to Unravel G-Quadruplex/Ligand Interactions

2021 ◽  
Vol 14 (8) ◽  
pp. 769
Author(s):  
Tiago Santos ◽  
Gilmar F. Salgado ◽  
Eurico J. Cabrita ◽  
Carla Cruz
Keyword(s):  
High Throughput ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Binding Mode ◽  
Titration Calorimetry ◽  
Apparent Affinity ◽  
G Quadruplex ◽  
Ligand Interactions ◽  
Types Of Information ◽  
Fluorescent Intercalator Displacement

Progress in the design of G-quadruplex (G4) binding ligands relies on the availability of approaches that assess the binding mode and nature of the interactions between G4 forming sequences and their putative ligands. The experimental approaches used to characterize G4/ligand interactions can be categorized into structure-based methods (circular dichroism (CD), nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography), affinity and apparent affinity-based methods (surface plasmon resonance (SPR), isothermal titration calorimetry (ITC) and mass spectrometry (MS)), and high-throughput methods (fluorescence resonance energy transfer (FRET)-melting, G4-fluorescent intercalator displacement assay (G4-FID), affinity chromatography and microarrays. Each method has unique advantages and drawbacks, which makes it essential to select the ideal strategies for the biological question being addressed. The structural- and affinity and apparent affinity-based methods are in several cases complex and/or time-consuming and can be combined with fast and cheap high-throughput approaches to improve the design and development of new potential G4 ligands. In recent years, the joint use of these techniques permitted the discovery of a huge number of G4 ligands investigated for diagnostic and therapeutic purposes. Overall, this review article highlights in detail the most commonly used approaches to characterize the G4/ligand interactions, as well as the applications and types of information that can be obtained from the use of each technique.

scholarly journals Selective Binding of Distamycin A Derivative to G-Quadruplex Structure [d(TGGGGT)]4

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Bruno Pagano ◽  
Iolanda Fotticchia ◽  
Stefano De Tito ◽  
Carlo A. Mattia ◽  
Luciano Mayol ◽  
...  
Keyword(s):  
Small Molecules ◽  
Titration Calorimetry ◽  
Distamycin A ◽  
Structural Modifications ◽  
Telomerase Inhibitors ◽  
G Quadruplex ◽  
Nmr Techniques ◽  
Eukaryotic Organisms ◽  
New Anticancer Drugs ◽  
Binding Behaviour

Guanine-rich nucleic acid sequences can adopt G-quadruplex structures stabilized by layers of four Hoogsteen-paired guanine residues. Quadruplex-prone sequences are found in many regions of human genome and in the telomeres of all eukaryotic organisms. Since small molecules that target G-quadruplexes have been found to be effective telomerase inhibitors, the identification of new specific ligands for G-quadruplexes is emerging as a promising approach to develop new anticancer drugs. Distamycin A is known to bind to AT-rich sequences of duplex DNA, but it has recently been shown to interact also with G-quadruplexes. Here, isothermal titration calorimetry (ITC) and NMR techniques have been employed to characterize the interaction between a dicationic derivative of distamycin A (compound1) and the [d(TGGGGT)]4quadruplex. Additionally, to compare the binding behaviour of netropsin and compound1to the same target, a calometric study of the interaction between netropsin and [d(TGGGGT)]4has been performed. Experiments show that netropsin and compound1are able to bind to [d(TGGGGT)]4with good affinity and comparable thermodynamic profiles. In both cases the interactions are entropically driven processes with a small favourable enthalpic contribution. Interestingly, the structural modifications of compound1decrease the affinity of the ligand toward the duplex, enhancing the selectivity.

scholarly journals On the interaction of an anticancer trisubstituted naphthalene diimide with G-quadruplexes of different topologies: a structural insight

2020 ◽  
Vol 48 (21) ◽  
pp. 12380-12393
Author(s):  
Chiara Platella ◽  
Marko Trajkovski ◽  
Filippo Doria ◽  
Mauro Freccero ◽  
Janez Plavec ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Dissociation Constants ◽  
Therapeutic Potential ◽  
In Vivo Studies ◽  
Binding Modes ◽  
Hybrid Topology ◽  
Naphthalene Diimide ◽  
G Quadruplex ◽  
Naphthalene Diimides

Abstract Naphthalene diimides showed significant anticancer activity in animal models, with therapeutic potential related to their ability to strongly interact with G-quadruplexes. Recently, a trifunctionalized naphthalene diimide, named NDI-5, was identified as the best analogue of a mini-library of novel naphthalene diimides for its high G-quadruplex binding affinity along with marked, selective anticancer activity, emerging as promising candidate drug for in vivo studies. Here we used NMR, dynamic light scattering, circular dichroism and fluorescence analyses to investigate the interactions of NDI-5 with G-quadruplexes featuring either parallel or hybrid topology. Interplay of different binding modes of NDI-5 to G-quadruplexes was observed for both parallel and hybrid topologies, with end-stacking always operative as the predominant binding event. While NDI-5 primarily targets the 5′-end quartet of the hybrid G-quadruplex model (m-tel24), the binding to a parallel G-quadruplex model (M2) occurs seemingly simultaneously at the 5′- and 3′-end quartets. With parallel G-quadruplex M2, NDI-5 formed stable complexes with 1:3 DNA:ligand binding stoichiometry. Conversely, when interacting with hybrid G-quadruplex m-tel24, NDI-5 showed multiple binding poses on a single G-quadruplex unit and/or formed different complexes comprising two or more G-quadruplex units. NDI-5 produced stabilizing effects on both G-quadruplexes, forming complexes with dissociation constants in the nM range.

Molecular Crowding Regulates the Structural Switch of the DNA G-Quadruplex†

Biochemistry ◽  
2002 ◽  
Vol 41 (50) ◽  
pp. 15017-15024 ◽  
Author(s):  
Daisuke Miyoshi ◽  
Akihiro Nakao ◽  
Naoki Sugimoto
Keyword(s):  
Molecular Crowding ◽  
G Quadruplex

Incorporation of O6-methylguanine restricts the conformational conversion of the human telomere G-quadruplex under molecular crowding conditions

2016 ◽  
Vol 52 (9) ◽  
pp. 1903-1906 ◽  
Author(s):  
Andong Zhao ◽  
Chuanqi Zhao ◽  
Hisae Tateishi-Karimata ◽  
Jinsong Ren ◽  
Naoki Sugimoto ◽  
...  
Keyword(s):  
Parallel Structure ◽  
Molecular Crowding ◽  
G Quadruplex ◽  
Human Telomere ◽  
Conformational Conversion

O6-methylguanine incorporation impeded the conformational conversion of G-quadruplex from a hybrid to a parallel structure under molecular crowding conditions.

scholarly journals The Effects of Molecular Crowding on the Structure and Stability of G-Quadruplexes with an Abasic Site

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Takeshi Fujimoto ◽  
Shu-ichi Nakano ◽  
Daisuke Miyoshi ◽  
Naoki Sugimoto
Keyword(s):  
Site Effects ◽  
Enthalpy Change ◽  
Molecular Crowding ◽  
Abasic Site ◽  
Structure And Stability ◽  
Quadruplex Structure ◽  
Abasic Sites ◽  
Crowding Effects ◽  
G Quadruplex ◽  
Quadruplex Formation

Both cellular environmental factors and chemical modifications critically affect the properties of nucleic acids. However, the structure and stability of DNA containing abasic sites under cell-mimicking molecular crowding conditions remain unclear. Here, we investigated the molecular crowding effects on the structure and stability of the G-quadruplexes including a single abasic site. Structural analysis by circular dichroism showed that molecular crowding by PEG200 did not affect the topology of the G-quadruplex structure with or without an abasic site. Thermodynamic analysis further demonstrated that the degree of stabilization of the G-quadruplex by molecular crowding decreased with substitution of an abasic site for a single guanine. Notably, we found that the molecular crowding effects on the enthalpy change for G-quadruplex formation had a linear relationship with the abasic site effects depending on its position. These results are useful for predicting the structure and stability of G-quadruplexes with abasic sites in the cell-mimicking conditions.

PURIFICATION OF LYSOZYME BY INTRINSICALLY SHIELDED HYDROGEL BEADS

2013 ◽  
Vol 27 (19) ◽  
pp. 1341028
Author(s):  
CONG LI ◽  
R. ZHANG ◽  
L. WANG ◽  
A. BOWYER ◽  
R. EISENTHAL ◽  
...  
Keyword(s):  
Binary Mixture ◽  
High Purity ◽  
High Selectivity ◽  
Egg White ◽  
Titration Calorimetry ◽  
Binding Affinities ◽  
Affinity Separation ◽  
Hydrogel Beads ◽  
Relative Binding ◽  
Very High

Macro-sized intrinsically shielded hydrogel beads have been prepared from BSA and CM-dextran grafted with CB using a technique based on freeze-thawing gelation method. The size of the beads lies in around 500 μm. Isothemal titration calorimetry (ITC) showed that the relative binding affinities of the lysozyme for CB, compared with BSA, at pH 3.0 was stronger than that at pH 7.4. They were employed for the affinity separation of lysozyme using chromatography column. Their adsorption capacity for lysozyme at pH 3.0 is higher than that at pH 9. In a binary mixture of lysozyme and ovalbumin, the beads showed very high selectivity toward lysozyme. Lysozyme of very high purity (> 93%) was obtained from a mixture of lysozyme and ovalbumin, and 85% from egg white solution. The results indicate that the macro-sized bead can be used for the separation, purification, and recovery of lysozyme in a chromatograph column.

scholarly journals Secondary Structural Preferences of Some Antibacterial Cyclooctapeptides in the Presence of Calcium(II)

2012 ◽  
Vol 2012 ◽  
pp. 1-10
Author(s):  
Tarshona Stevens ◽  
Nykia McNeil ◽  
Xiuli Lin ◽  
Maria Ngu-Schwemlein
Keyword(s):  
Antibacterial Activity ◽  
Absorption Band ◽  
Titration Calorimetry ◽  
Conformational Structure ◽  
Binding Affinities ◽  
Beta Sheet ◽  
Antibacterial Compounds ◽  
Weak Binding ◽  
Beta Sheet Structure ◽  
Structural Preferences

The purpose of this study is to understand the interactions of some antibacterial cationic amphipathic cyclooctapeptides with calcium(II) and their secondary structural preferences. The thermodynamic parameters associated with calcium(II) interactions, between the antibacterial active cyclooctapeptides (COP 1–6) and those that did not exhibit significant activities (COP 7–9), were studied by isothermal titration calorimetry. Calcium(II) binding in the absence and presence of micellar dodecylphosphocholine (DPC), a membrane mimicking detergent, was conducted by circular dichroism (CD). Both groups of cyclopeptides showed weak binding affinities for calcium(II) (Kb ca. 10−3 M−1). However, CD data showed that the antimicrobial peptides COP 1–6 adopted a twisted beta-sheet structure (positive CD absorption band at ca. 203 nm) in the presence of calcium(II) in micellar DPC. In contrast, COP 7–9, which lacked antibacterial activity, adopted a different conformational structure (negative CD absorption band at ca. 203 nm). These results indicate that these cyclopeptides could adopt secondary structural preferences in the presence of calcium(II) amidst a hydrophobic environment to elicit their antibacterial activity. These findings could be useful in facilitating the design of cyclopeptide derivatives that can adopt this beta-sheet-like secondary structure and, thereby, provide a useful molecular template for crafting antibacterial compounds.

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