scholarly journals Binding of BRACO19 to a Telomeric G-Quadruplex DNA Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1010 ◽  
Author(s):  
Babitha Machireddy ◽  
Holli-Joi Sullivan ◽  
Chun Wu
Keyword(s):  
Molecular Dynamics ◽  
Binding Energy ◽  
Free Ligand ◽  
Binding Mode ◽  
Dna Duplex ◽  
Telomeric Dna ◽  
Groove Binding ◽  
Relative Population ◽  
G Quadruplex ◽  
Groove Binding Mode

Although BRACO19 is a potent G-quadruplex binder, its potential for clinical usage is hindered by its low selectivity towards DNA G-quadruplex over duplex. High-resolution structures of BRACO19 in complex with neither single-stranded telomeric DNA G-quadruplexes nor B-DNA duplex are available. In this study, the binding pathway of BRACO19 was probed by 27.5 µs molecular dynamics binding simulations with a free ligand (BRACO19) to a DNA duplex and three different topological folds of the human telomeric DNA G-quadruplex (parallel, anti-parallel and hybrid). The most stable binding modes were identified as end stacking and groove binding for the DNA G-quadruplexes and duplex, respectively. Among the three G-quadruplex topologies, the MM-GBSA binding energy analysis suggested that BRACO19′s binding to the parallel scaffold was most energetically favorable. The two lines of conflicting evidence plus our binding energy data suggest conformation-selection mechanism: the relative population shift of three scaffolds upon BRACO19 binding (i.e., an increase of population of parallel scaffold, a decrease of populations of antiparallel and/or hybrid scaffold). This hypothesis appears to be consistent with the fact that BRACO19 was specifically designed based on the structural requirements of the parallel scaffold and has since proven effective against a variety of cancer cell lines as well as toward a number of scaffolds. In addition, this binding mode is only slightly more favorable than BRACO19s binding to the duplex, explaining the low binding selectivity of BRACO19 to G-quadruplexes over duplex DNA. Our detailed analysis suggests that BRACO19′s groove binding mode may not be stable enough to maintain a prolonged binding event and that the groove binding mode may function as an intermediate state preceding a more energetically favorable end stacking pose; base flipping played an important role in enhancing binding interactions, an integral feature of an induced fit binding mechanism.

scholarly journals Forever Young: Structural Stability of Telomeric Guanine-Quadruplexes in Presence of Oxidative DNA Lesions

2020 ◽  
Author(s):  
Tom Miclot ◽  
Camille Corbier ◽  
Alessio Terenzi ◽  
Cécilia Hognon ◽  
Stéphanie Grandemange ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Dynamics ◽  
Structural Stability ◽  
Md Simulations ◽  
Dna Lesions ◽  
Computational Investigation ◽  
Telomeric Dna ◽  
G Quadruplex ◽  
The Stability

AbstractHuman telomeric DNA (h-Telo), in G-quadruplex (G4) conformation, is characterized by a remarkable structural stability that confers it the capacity to resist to oxidative stress producing one or even clustered 8-oxoguanine lesions. We present a combined experimental/computational investigation, by using circular dichroism in aqueous solutions, cellular immunofluorescence assays and molecular dynamics (MD) simulations, that identifies the crucial role of the stability of G4s to oxidative lesions, related also to their biological role as inhibitors of telomerase, an enzyme overexpressed in most cancers associated to oxidative stress.

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.

Primary photoprocesses in cationic 5,10,15,20-meso-tetrakis(4-N-methylpyridiniumyl)porphyrin and its transition metal complexes bound with nucleic acids

2003 ◽  
Vol 07 (11) ◽  
pp. 766-774 ◽  
Author(s):  
Vladimir S. Chirvony
Keyword(s):  
Excited States ◽  
Transition Metal Complexes ◽  
Photophysical Properties ◽  
Binding Mode ◽  
Axial Ligand ◽  
Guanosine Monophosphate ◽  
Groove Binding ◽  
Base Pairs ◽  
Excited Complex ◽  
Groove Binding Mode

Photophysical properties of meso-tetrakis(4-N-methylpyridiniumyl)porphyrin ( TMpyP 4) and its metallocomplexes M (II) TMpy P4 ( M = Zn , Cu , Ni , Co ) bound to natural DNA and synthetic poly-, oligo- and mononucleotides are considered with a primary emphasis placed upon intermolecular interaction of the photoexcited porphyrins with the nearest environment. Quenching of the fluorescent S 1 (but not triplet T 1) state due to guanine to porphyrin electron transfer is observed for TMpyP 4 intercalated between GC base pairs of the double-strand helixes, whereas in the case of TMpyP 4 complexed with guanosine monophosphate (GMP) both S 1 and T 1 states of the porphyrin are quenched. Furthermore, a dependence of the efficiency of TMpyP 4 triplet state quenching by the dissolved molecular oxygen from air on the porphyrin localization enables one to readily distinguish porphyrin groove binding mode from intercalation. Excited states of the TMpyP 4 complexes with transition metals, in spite of their very short lifetimes, also interact with nucleic acid components by means of an axial ligand binding/release to/from the metal. A possible structure of the five-coordinate excited complex (“exciplex”) formed in case of CuTMpyP 4 groove binding to some single- and double-strand polynucleotides is discussed.

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 Molecular Dynamics Study of the Interaction of Carbon Nanotubes with Telomeric DNA Fragment Containing Noncanonical G-Quadruplex and i-Motif Forms

2020 ◽  
Vol 21 (6) ◽  
pp. 1925 ◽  
Author(s):  
Tomasz Panczyk ◽  
Patrycja Wojton ◽  
Pawel Wolski
Keyword(s):  
Carbon Nanotubes ◽  
Molecular Dynamics ◽  
Spatial Structure ◽  
Computational Procedure ◽  
Middle Part ◽  
Telomeric Dna ◽  
Neutral Ph ◽  
G Quadruplex ◽  
The Stability ◽  
Dynamics Simulations

This work deals with molecular dynamics simulations of systems composed of telomeric dsDNA fragments, iG, and functionalized carbon nanotubes, fCNT. The iG contains 90 nucleotides in total and in its middle part the noncanonical i-motif and G-quadruplex are formed. Two chiralities of the fCNT were used, i.e., (10,0) and (20,0) and these nanotubes were either on-tip functionalized by guanine containing functional groups or left without functionalization. We proposed a dedicated computational procedure, based on the replica exchange concept, for finding a thermodynamically optimal conformation of iG and fCNT without destroying the very fragile noncanonical parts of the iG. We found that iG forms a V-shape spatial structure with the noncanonical fragments located at the edge and the remaining dsDNA strands forming the arms of V letter. The optimal configuration of iG in reference to fCNT strongly depends on the on-tip functionalization of the fCNT. The carbon nanotube without functionalization moves freely between the dsDNA arms, while the presence of guanine residues leads to immobilization of the fCNT and preferential location of the nanotube tip near the junction between the dsDNA duplex and i-motif and G-quadruplex. We also studied how the presence of fCNT affects the stability of the i-motif at the neutral pH when the cytosine pairs are nonprotonated. We concluded that carbon nanotubes do not improve the stability of the spatial structure of i-motif also when it is a part of a bigger structure like the iG. Such an effect was described in literature in reference to carboxylated nanotubes. Our current results suggest that the stabilization of i-motif is most probably related to easy formation of semiprotonated cytosine pairs at neutral pH due to interaction with carboxylated carbon nanotubes.

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