scholarly journals The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base Pairs

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
William H. Gmeiner ◽  
Freddie Salsbury ◽  
Chris M. Olsen ◽  
Luis A. Marky
Keyword(s):  
Base Pair ◽  
Cleavage Site ◽  
Nucleoside Analogs ◽  
Dna Duplex ◽  
Base Pairs ◽  
Topoisomerase 1 ◽  
Mismatched Base Pair ◽  
The Stability ◽  
Dynamics Simulations ◽  
Dna Complex

Topoisomerase 1 (Top1) enzymes regulate DNA superhelicity by forming covalent cleavage complexes that undergo controlled rotation. Substitution of nucleoside analogs at the +1 position of the DNA duplex relative to the Top1 cleavage site inhibits DNA religation. The reduced efficiency for Top1-mediated religation contributes to the anticancer activity of widely used anticancer drugs including fluoropyrimidines and gemcitabine. In the present study, we report that mismatched base pairs at the +1 position destabilize the duplex DNA components for a model Top1 cleavage complex formation even though one duplex component does not directly include a mismatched base pair. Molecular dynamics simulations reveal G-dU and G-FdU mismatched base pairs, but not a G-T mismatched base pair, increase flexibility at the Top1 cleavage site, and affect coupling between the regions required for the religation reaction to occur. These results demonstrate that substitution of dT analogs into the +1 position of the non-scissile strand alters the stability and flexibility of DNA contributing to the reduced efficiency for Top1-mediated DNA religation. These effects are inherent in the DNA duplex and do not require formation of the Top1:DNA complex. These results provide a biophysical rationale for the inhibition of Top1-mediated DNA religation by nucleotide analog substitution.

scholarly journals Supercoiling DNA locates mismatches

2017 ◽  
Author(s):  
Andrew Dittmore ◽  
Sumitabha Brahmachari ◽  
Yasuhara Takagi ◽  
John F. Marko ◽  
Keir C. Neuman
Keyword(s):  
Dna Sequence ◽  
Base Pair ◽  
Dna Supercoiling ◽  
Magnetic Tweezers ◽  
Relative Probability ◽  
Base Pairs ◽  
Damage Sensing ◽  
Mismatched Base Pair ◽  
Monovalent Salt

We present a method of detecting sequence defects by supercoiling DNA with magnetic tweezers. The method is sensitive to a single mismatched base pair in a DNA sequence of several thousand base pairs. We systematically compare DNA molecules with 0 to 16 adjacent mismatches at 1 M monovalent salt and 3.5 pN force and show that, under these conditions, a single plectoneme forms and is stably pinned at the defect. We use these measurements to estimate the energy and degree of end-loop kinking at defects. From this, we calculate the relative probability of plectoneme pinning at the mismatch under physiologically relevant conditions. Based on this estimate, we propose that DNA supercoiling could contribute to mismatch and damage sensing in vivo.

scholarly journals Halogen-Bonded Guanine Base Pairs, Quartets and Ribbons

2020 ◽  
Vol 21 (18) ◽  
pp. 6571
Author(s):  
Nicholas J. Thornton ◽  
Tanja van Mourik
Keyword(s):  
Base Pair ◽  
Halogen Bond ◽  
Halogen Bonding ◽  
Dna Bases ◽  
Halogen Bonds ◽  
Base Pairs ◽  
Rich Diversity ◽  
Different Types ◽  
Guanine Base ◽  
The Stability

Halogen bonding is studied in different structures consisting of halogenated guanine DNA bases, including the Hoogsteen guanine–guanine base pair, two different types of guanine ribbons (R-I and R-II) consisting of two or three monomers, and guanine quartets. In the halogenated base pairs (except the Cl-base pair, which has a very non-planar structure with no halogen bonds) and R-I ribbons (except the At trimer), the potential N-X•••O interaction is sacrificed to optimise the N-X•••N halogen bond. In the At trimer, the astatines originally bonded to N1 in the halogen bond donating guanines have moved to the adjacent O6 atom, enabling O-At•••N, N-At•••O, and N-At•••At halogen bonds. The brominated and chlorinated R-II trimers contain two N-X•••N and two N-X•••O halogen bonds, whereas in the iodinated and astatinated trimers, one of the N-X•••N halogen bonds is lost. The corresponding R-II dimers keep the same halogen bond patterns. The G-quartets display a rich diversity of symmetries and halogen bond patterns, including N-X•••N, N-X•••O, N-X•••X, O-X•••X, and O-X•••O halogen bonds (the latter two facilitated by the transfer of halogens from N1 to O6). In general, halogenation decreases the stability of the structures. However, the stability increases with the increasing atomic number of the halogen, and the At-doped R-I trimer and the three most stable At-doped quartets are more stable than their hydrogenated counterparts. Significant deviations from linearity are found for some of the halogen bonds (with halogen bond angles around 150°).

scholarly journals Use of Nucleic Acid Analogs for the Study of Nucleic Acid Interactions

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Shu-ichi Nakano ◽  
Masayuki Fujii ◽  
Naoki Sugimoto
Keyword(s):  
Nucleic Acid ◽  
Base Pair ◽  
Double Helix ◽  
Nucleoside Analogs ◽  
Structural Analog ◽  
Base Pairs ◽  
Nucleic Acid Analogs ◽  
Dna Double Helix ◽  
Nucleic Acid Interactions ◽  
Site Selective

Unnatural nucleosides have been explored to expand the properties and the applications of oligonucleotides. This paper briefly summarizes nucleic acid analogs in which the base is modified or replaced by an unnatural stacking group for the study of nucleic acid interactions. We also describe the nucleoside analogs of a base pair-mimic structure that we have examined. Although the base pair-mimic nucleosides possess a simplified stacking moiety of a phenyl or naphthyl group, they can be used as a structural analog of Watson-Crick base pairs. Remarkably, they can adopt two different conformations responding to their interaction energies, and one of them is the stacking conformation of the nonpolar aromatic group causing the site-selective flipping of the opposite base in a DNA double helix. The base pair-mimic nucleosides can be used to study the mechanism responsible for the base stacking and the flipping of bases out of a nucleic acid duplex.

scholarly journals Crystallographic evidence of Watson–Crick connectivity in the base pair of anionic adenine with thymine

2020 ◽  
Vol 117 (31) ◽  
pp. 18224-18230
Author(s):  
Manish Kumar Mishra ◽  
Steven P. Kelley ◽  
Volodymyr Smetana ◽  
David A. Dixon ◽  
Ashley S. McNeill ◽  
...  
Keyword(s):  
Gas Phase ◽  
Base Pair ◽  
Phase Reaction ◽  
Base Pairs ◽  
Gas Phase Reaction ◽  
Neutral Base ◽  
The Stability ◽  
Structure Calculations ◽  
Insight Into ◽  
Stable Formation

Utilizing an ionic liquid strategy, we report crystal structures of salts of free anionic nucleobases and base pairs previously studied only computationally and in the gas phase. Reaction of tetrabutylammonium ([N4444]+) or tetrabutylphosphonium ([P4444]+) hydroxide with adenine (HAd) and thymine (HThy) led to hydrated salts of deprotonated adenine, [N4444][Ad]·2H2O, and thymine, [P4444][Thy]·2H2O, as well as the double salt cocrystal, [P4444]2[Ad][Thy]·3H2O·2HThy. The cocrystal includes the anionic [Ad−(HThy)] base pair which is a stable formation in the solid state that has previously not even been suggested. It exhibits Watson–Crick connectivity as found in DNA but which is unusual for the free neutral base pairs. The stability of the observed anionic bases and their supramolecular formations and hydrates has also been examined by electronic structure calculations, contributing to more insight into how base pairs can bind when a proton is removed and highlighting mechanisms of stabilization or chemical transformation in the DNA chains.

QUANTUM MECHANICAL DESCRIPTION OF THE INTERACTIONS BETWEEN DNA AND 9,10-ANTHRAQUINONE

2008 ◽  
Vol 07 (03) ◽  
pp. 317-329 ◽  
Author(s):  
SIAVASH RIAHI ◽  
MOHAMMAD REZA GANJALI ◽  
PARVIZ NOROUZI
Keyword(s):  
Base Pair ◽  
Dft Method ◽  
Base Pairs ◽  
Dispersion Energy ◽  
Charge Delocalization ◽  
Dna Base ◽  
Quantum Mechanical Description ◽  
London Dispersion ◽  
Dna Base Pair ◽  
The Stability

Molecular geometries of the 9,10-anthraquinone (AQ) and DNA bases (Adenine, Guanine, Cytosine, and Thymine) were optimized using B3LYP/6-31G** method. Properties of isolated intercalator (9,10-anthraquinone) and their stacking interactions with adenine ⋯ thymine (AT) and guanine ⋯ cytosine (GC) nucleic acid base pairs were investigated by means of DFTB method. DFTB method, an approximate version of the DFT method, was extended to cover London dispersion energy. AQ exhibits a large charge delocalization and it has no site with dominant charge. This intercalator has a large polarizability and is a good electron acceptor, while base pairs are good electron donors. B3LYP/6-31G** stabilization energies of intercalator ⋯ base pair complexes are large (-18.83 kcal/mol for AT ⋯ AQ and -15.69 kcal/mol for GC ⋯ AQ). It is concluded that, the dispersion energy predominantly contributes to the stability of intercalator ⋯ DNA base pair complexes. Any procedure which does not cover dispersion energy is thus not suitable for studying the process of intercalation. The results showed that AQ changes the structure of DNA on bond length, bond angle, torsion angle, and charges.

scholarly journals Effects of Stability of Base Pairs Containing an Oxazolone on DNA Elongation

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Masayo Suzuki ◽  
Kazuya Ohtsuki ◽  
Katsuhito Kino ◽  
Teruhiko Kobayashi ◽  
Masayuki Morikawa ◽  
...  
Keyword(s):  
Dna Replication ◽  
Oxidative Damage ◽  
Ab Initio ◽  
Base Pair ◽  
Thermal Denaturation ◽  
Primer Extension ◽  
Base Pairs ◽  
Nucleotide Incorporation ◽  
The Stability

The nucleoside 2,2,4-triamino-5(2H)-oxazolone (Oz) can result from oxidative damage to guanine residues in DNA. Despite differences among the three polymerases (Polβ, KF exo−, and Polη) regarding nucleotide incorporation patterns opposite Oz, all three polymerases can incorporate guanine opposite Oz. Based onab initiocalculations, we proposed a structure for a stable Oz:G base pair. Here, to assess the stability of each Oz-containing base pair (Oz:G, Oz:A, Oz:C, and Oz:T) upon DNA replication, we determined the efficiency of Polβ-, KF exo−-, or Polη-catalyzed primer extension beyond each base pair. With each polymerase, extension beyond Oz:G was more efficient than that beyond Oz:A, Oz:C, or Oz:T. Moreover, thermal denaturation studies revealed that theTmvalue for the duplex containing Oz:G was significantly higher than those obtained for duplexes containing Oz:A, Oz:C, or Oz:T. Therefore, the results fromab initiocalculations along with those from DNA replication assays and thermal denaturation experiments supported the conclusion that Oz:G is the most stable of the Oz-containing base pairs.

scholarly journals Second generation silver(I)-mediated imidazole base pairs

2014 ◽  
Vol 10 ◽  
pp. 2139-2144 ◽  
Author(s):  
Susanne Hensel ◽  
Nicole Megger ◽  
Kristina Schweizer ◽  
Jens Müller
Keyword(s):  
Thermal Stability ◽  
Melting Temperature ◽  
Base Pair ◽  
Metal Ion ◽  
Second Generation ◽  
Dna Duplex ◽  
Base Pairs ◽  
Double Helices ◽  
Thermal Stability Of

The imidazole–Ag(I)–imidazole base pair is one of the best-investigated artificial metal-mediated base pairs. We show here that its stability can be further improved by formally replacing the imidazole moiety by a 2-methylimidazole or 4-methylimidazole moiety. A comparison of the thermal stability of several double helices shows that the addition of one equivalent of Ag(I) leads to a 50% larger increase in the melting temperature when a DNA duplex with methylated imidazole nucleosides is applied. This significant effect can likely be attributed to a better steric shielding of the metal ion within the metal-mediated base pair.

scholarly journals Dynamic Structure and Stability of DNA Duplexes Bearing a Dinuclear Hg(II)-Mediated Base Pair

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4942
Author(s):  
Jim Bachmann ◽  
Isabell Schönrath ◽  
Jens Müller ◽  
Nikos L. Doltsinis
Keyword(s):  
Base Pair ◽  
Metal Ion ◽  
Model Building ◽  
Dynamic Structure ◽  
Quantum Mechanical ◽  
Distance Constraint ◽  
Dna Duplexes ◽  
Base Pairs ◽  
Intramolecular Bonding ◽  
Dynamics Simulations

Quantum mechanical (QM) and hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations of a recently reported dinuclear mercury(II)-mediated base pair were performed aiming to analyse its intramolecular bonding pattern, its stability, and to obtain clues on the mechanism of the incorporation of mercury(II) into the DNA. The dynamic distance constraint was employed to find initial structures, control the dissociation process in an unbiased fashion and to determine the free energy required. A strong influence of the exocyclic carbonyl or amino groups of neighbouring base pairs on both the bonding pattern and the mechanism of incorporation was observed. During the dissociation simulation, an amino group of an adenine moiety of the adjacent base pair acts as a turnstile to rotate the mercury(II) ion out of the DNA core region. The calculations provide an important insight into the mechanism of formation of this dinuclear metal-mediated base pair and indicate that the exact location of a transition metal ion in a metal-mediated base pair may be more ambiguous than derived from simple model building.

scholarly journals Ethidium bromide interactions with DNA: an exploration of a classic DNA–ligand complex with unbiased molecular dynamics simulations

2021 ◽  
Vol 49 (7) ◽  
pp. 3735-3747
Author(s):  
Rodrigo Galindo-Murillo ◽  
Thomas E Cheatham
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Ethidium Bromide ◽  
Base Pair ◽  
Force Fields ◽  
Ligand Complex ◽  
Base Pairs ◽  
Duplex System ◽  
Double Stranded Dna ◽  
Dynamics Simulations

Abstract Visualization of double stranded DNA in gels with the binding of the fluorescent dye ethidium bromide has been a basic experimental technique in any molecular biology laboratory for >40 years. The interaction between ethidium and double stranded DNA has been observed to be an intercalation between base pairs with strong experimental evidence. This presents a unique opportunity for computational chemistry and biomolecular simulation techniques to benchmark and assess their models in order to see if the theory can reproduce experiments and ultimately provide new insights. We present molecular dynamics simulations of the interaction of ethidium with two different double stranded DNA models. The first model system is the classic sequence d(CGCGAATTCGCG)2 also known as the Drew–Dickerson dodecamer. We found that the ethidium ligand binds mainly stacked on, or intercalated between, the terminal base pairs of the DNA with little to no interaction with the inner base pairs. As the intercalation at the terminal CpG steps is relatively rapid, the resultant DNA unwinding, rigidification, and increased stability of the internal base pair steps inhibits further intercalation. In order to reduce these interactions and to provide a larger groove space, a second 18-mer DNA duplex system with the sequence d(GCATGAACGAACGAACGC) was tested. We computed molecular dynamics simulations for 20 independent replicas with this sequence, each with ∼27 μs of sampling time. Results show several spontaneous intercalation and base-pair eversion events that are consistent with experimental observations. The present work suggests that extended MD simulations with modern DNA force fields and optimized simulation codes are allowing the ability to reproduce unbiased intercalation events that we were not able to previously reach due to limits in computing power and the lack of extensively tested force fields and analysis tools.

scholarly journals Effect of Potassium Concentration on Triplex Stability under Molecular Crowding Conditions

Molecules ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 387 ◽  
Author(s):  
Ye Teng ◽  
Hisae Tateishi-Karimata ◽  
Tatsuya Ohyama ◽  
Naoki Sugimoto
Keyword(s):  
Base Pair ◽  
Potassium Concentration ◽  
Quantitative Information ◽  
Molecular Crowding ◽  
Dilute Solution ◽  
Base Pairs ◽  
Dna Structures ◽  
Dilute Aqueous Solutions ◽  
K Concentration ◽  
The Stability

The properties of non-canonical DNA structures, like G-quadruplexes and triplexes, change under cell-mimicking molecular crowding conditions relative to dilute aqueous solutions. The analysis of environmental effects on their stability is crucial since they play important roles in gene expression and regulation. In this study, three intramolecular and intermolecular triplex-forming sequences of different C+*G-C triplet content (*: Hoogsteen base pair; - : Watson–Crick base pair) were designed and their stability measured in the absence and presence of a crowding agent with different K+ concentrations. In dilute solution, the stability of the triplexes was reduced by decreasing the concentration of KCl. This reduction became smaller as the number of C+*G-C triplets increased. Under molecular crowding conditions, Watson–Crick base pairs and Hoogsteen base pairs were destabilized and stabilized, respectively. Interestingly, with lower KCl concentrations (≤1 M), the destabilization of the triplexes due to reduction of KCl concentration was significantly smaller than in dilute solutions. In addition, the C+*G-C content had greater influence on triplex stability under molecular crowding conditions. Our work provides quantitative information about the effects of K+ concentration on triplex stability under molecular crowding conditions and should further our understanding of the function and regulation of triplexes in bioprocesses.

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