G-Quadruplex and I-Motif Structures within the Telomeric DNA Duplex. A Molecular Dynamics Analysis of Protonation States as Factors Affecting Their Stability

2018 ◽  
Vol 123 (2) ◽  
pp. 468-479 ◽  
Author(s):  
Pawel Wolski ◽  
Krzysztof Nieszporek ◽  
Tomasz Panczyk
Keyword(s):  
Molecular Dynamics ◽  
Dynamics Analysis ◽  
Dna Duplex ◽  
Telomeric Dna ◽  
Factors Affecting ◽  
G Quadruplex

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 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.

Binding modes and pathway of RHPS4 to human telomeric G-quadruplex and duplex DNA probed by all-atom molecular dynamics simulations with explicit solvent

2017 ◽  
Vol 19 (28) ◽  
pp. 18685-18694 ◽  
Author(s):  
Kelly Mulholland ◽  
Farzana Siddiquei ◽  
Chun Wu
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Md Simulations ◽  
Duplex Dna ◽  
Binding Modes ◽  
Dna Duplex ◽  
Explicit Solvent ◽  
G Quadruplex ◽  
Dynamics Simulations

Binding modes ofRHPS4to DNA duplex and human teloemeric G-quadruplexes from MD simulations.

scholarly journals PhenQE8, a Novel Ligand of the Human Telomeric Quadruplex

2021 ◽  
Vol 22 (2) ◽  
pp. 749
Author(s):  
Patricia B. Gratal ◽  
Julia G. Quero ◽  
Adrián Pérez-Redondo ◽  
Zoila Gándara ◽  
Lourdes Gude
Keyword(s):  
Equilibrium Dialysis ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
The Novel ◽  
X Ray Diffraction ◽  
Telomeric Dna ◽  
Healthy Human ◽  
Quadruplex Dna ◽  
Step Procedure ◽  
G Quadruplex

A novel quadruplex ligand based on 1,10-phenanthroline and incorporating two guanyl hydrazone functionalities, PhenQE8, is reported herein. Synthetic access was gained in a two-step procedure with an overall yield of 61%. X-ray diffraction studies revealed that PhenQE8 can adopt an extended conformation that may be optimal to favor recognition of quadruplex DNA. DNA interactions with polymorphic G-quadruplex telomeric structures were studied by different techniques, such as Fluorescence resonance energy transfer (FRET) DNA melting assays, circular dichroism and equilibrium dialysis. Our results reveal that the novel ligand PhenQE8 can efficiently recognize the hybrid quadruplex structures of the human telomeric DNA, with high binding affinity and quadruplex/duplex selectivity. Moreover, the compound shows significant cytotoxic activity against a selected panel of cultured tumor cells (PC-3, HeLa and MCF-7), whereas its cytotoxicity is considerably lower in healthy human cells (HFF-1 and RPWE-1).

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