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 Bending of DNA duplexes with mutation motifs

DNA Research ◽  
2019 ◽  
Vol 26 (4) ◽  
pp. 341-352
Author(s):  
Michal Růžička ◽  
Přemysl Souček ◽  
Petr Kulhánek ◽  
Lenka Radová ◽  
Lenka Fajkusová ◽  
...  
Keyword(s):  
De Novo ◽  
Excision Repair ◽  
Dna Duplexes ◽  
De Novo Mutations ◽  
Base Pairs ◽  
Inherited Disorders ◽  
Cpg Dinucleotides ◽  
Human Genes ◽  
Base Excision ◽  
Dynamics Simulations

Abstract Mutations can be induced by environmental factors but also arise spontaneously during DNA replication or due to deamination of methylated cytosines at CpG dinucleotides. Sites where mutations occur with higher frequency than would be expected by chance are termed hotspots while sites that contain mutations rarely are termed coldspots. Mutations are permanently scanned and repaired by repair systems. Among them, the mismatch repair targets base pair mismatches, which are discriminated from canonical base pairs by probing altered elasticity of DNA. Using biased molecular dynamics simulations, we investigated the elasticity of coldspots and hotspots motifs detected in human genes associated with inherited disorders, and also of motifs with Czech population hotspots and de novo mutations. Main attention was paid to mutations leading to G/T and A+/C pairs. We observed that hotspots without CpG/CpHpG sequences are less flexible than coldspots, which indicates that flexible sequences are more effectively repaired. In contrary, hotspots with CpG/CpHpG sequences exhibited increased flexibility as coldspots. Their mutability is more likely related to spontaneous deamination of methylated cytosines leading to C > T mutations, which are primarily targeted by base excision repair. We corroborated conclusions based on computer simulations by measuring melting curves of hotspots and coldspots containing G/T mismatch.

scholarly journals Enzymatic Formation of an Artificial Base Pair Using a Modified Adenine Nucleoside Triphosphate

2019 ◽  
Author(s):  
Marie Flamme ◽  
Pascal Röthlisberger ◽  
Fabienne Levi-Acobas ◽  
Mohit Chawla ◽  
Romina Oliva ◽  
...  
Keyword(s):  
Base Pair ◽  
In Vitro Selection ◽  
Solid Phase ◽  
Nucleoside Triphosphate ◽  
Dna Duplexes ◽  
Base Pairs ◽  
Metal Base ◽  
Enzymatic Formation ◽  
Genetic Alphabet

The expansion of the genetic alphabet with additional, unnatural base pairs (UBPs) is an important and long standing goal in synthetic biology. Nucleotides acting as ligands for the coordination of metal cations have advanced as promising candidates for such an expansion of the genetic alphabet. However,the inclusion of artificial metal base pairs in nucleic acids mainly relies on solid-phase synthesis approaches and very little is known on polymerase-mediated synthesis. Herein, we report on the selective and high yielding enzymatic construction of a silver-mediated base pair as well as a two-step protocol for the synthesis of DNA duplexes containing a metal UBP. Guided by DFT calculations, we also shed light into the mechanism of formation of this UBP as well as into the structural and energetic preferences. Even though this silver UBP is not directly amenable to in vitro selection experiments, the enzymatic synthesis of this UBP provides valuable insights for the design of future, more potent systems aiming at expanding the genetic alphabet. <br>

scholarly journals A Quantum-Mechanical Looking Behind the Scene of the Classic G·C Nucleobase Pairs Tautomerization

2020 ◽  
Vol 8 ◽  
Author(s):  
Ol'ha O. Brovarets' ◽  
Alona Muradova ◽  
Dmytro M. Hovorun
Keyword(s):  
Base Pair ◽  
Double Helix ◽  
Ion Pairs ◽  
Electronic Energy ◽  
Tautomeric Equilibrium ◽  
Chemical Mechanism ◽  
Hydroxyl Group ◽  
Quantum Mechanical ◽  
Base Pairs ◽  
Tautomeric Forms

For the first time, at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory, a comprehensive quantum-mechanical investigation of the physico-chemical mechanism of the tautomeric wobblization of the four biologically-important G·C nucleobase pairs by the participation of the monomers in rare, in particular mutagenic, tautomeric forms (marked with an asterisk) was provided. These novel tautomeric transformations (wobblization or shifting of the bases within the pair) are intrinsically inherent properties of the G·C nucleobase pairs. In this study, we have obtained intriguing results, lying far beyond the existing representations. Thus, it was shown that Löwdin's G*·C*(WC) base pair does not tautomerize according to the wobblization mechanism. Tautomeric wobblization of the G*·C*(rWC) (relative Gibbs free energy ΔG = 0.00/relative electronic energy ΔE = 0.00 kcal·mol−1) (“r”—means the configuration of the base pair in reverse position; “WC”—the classic Watson-Crick configuration) and G*t·C*(H) (ΔG = −0.19/ΔE = 0.29 kcal·mol−1) (“H”—Hoogsteen configuration;”t” denotes the O6H hydroxyl group in the trans position) base pairs are preceded by the stages of the base pairs tautomerization by the single proton transfer (SPT). It was established that the G*t·C*(rH) (ΔG = 2.21/ΔE = 2.81 kcal·mol−1) base pair can be wobbled through two different pathways via the traditional one-stage mechanism through the TSs, which are tight G+·C− ion pairs, stabilized by the participation of only two intermolecular H-bonds. It was found out that the G·C base pair is most likely incorporated into the DNA/RNA double helix with parallel strands in the G*·C*(rWC), G·C*(rwwc), and G*·C(rwwc) (“w”—wobble configuration of the pair) tautomeric forms, which are in rapid tautomeric equilibrium with each other. It was proven that the G*·C*(rWC) nucleobase pair is also in rapid tautomeric equilibrium with the eight tautomeric forms of the so-called Levitt base pair. It was revealed that a few cases of tautomerization via the DPT of the nucleobase pairs by the participation of the C8H group of the guanine had occurred. The biological role of the obtained results was also made apparent.

Metal ion-binding properties of DNA duplexes containing thiopyrimidine base pairs

2012 ◽  
Vol 48 (36) ◽  
pp. 4347 ◽  
Author(s):  
Itaru Okamoto ◽  
Takashi Ono ◽  
Rimi Sameshima ◽  
Akira Ono
Keyword(s):  
Metal Ion ◽  
Ion Binding ◽  
Dna Duplexes ◽  
Metal Ion Binding ◽  
Base Pairs ◽  
Binding Properties

scholarly journals Destabilization of DNA duplexes by oxidative damage at guanine: implications for lesion recognition and repair

2008 ◽  
Vol 5 (suppl_3) ◽  
pp. 191-198 ◽  
Author(s):  
Supat Jiranusornkul ◽  
Charles A Laughton
Keyword(s):  
Oxidative Damage ◽  
Structural Changes ◽  
Double Helix ◽  
Dependent Manner ◽  
Dna Duplexes ◽  
Lesion Site ◽  
Base Pairs ◽  
Energetic Analysis ◽  
Dynamics Simulations ◽  
Dna Double Helix

We have used molecular dynamics simulations to study the structure and dynamics of a range of DNA duplexes containing the 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapydG) lesion that can result from oxidative damage at guanine. Compared to the corresponding undamaged DNA duplexes, FapydG-containing duplexes show little gross structural changes—the damaged base remains stacked in to the DNA double helix and retains hydrogen bonds to its cytosine partner. However, the experimentally observed reduction in DNA stability that accompanies lesion formation can be explained by a careful energetic analysis of the simulation data. Irrespective of the nature of the base pairs on either side of the lesion site, conversion of a guanine to a FapydG base results in increased dynamical flexibility in the base (but not in the DNA as a whole) that significantly weakens its hydrogen-bonding interactions. Surprisingly, the stacking interactions with its neighbours are not greatly altered. The formamido group adopts a non-planar conformation that can interact significantly and in a sequence-dependent manner with its 3′-neighbour. We conclude that the recognition of FapydG lesions by the repair protein formamidopyrimidine-DNA glycosylase probably does not involve the protein capturing an already-extrahelical FapydG base, but rather it relies on detecting alterations to the DNA structure and flexibility created by the lesion site.

Syntheses and characterizations of DNA duplexes having metal ion mediated base pairs

2014 ◽  
Author(s):  
Akira Ono ◽  
Itaru Okamoto ◽  
Hideo Urata ◽  
Hidetake Torigoe ◽  
Hisao Saneyoshia ◽  
...  
Keyword(s):  
Metal Ion ◽  
Dna Duplexes ◽  
Base Pairs

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 Structural Landscape of the Transition from an ssDNA Dumbbell Plus Its Complementary Hairpin to a dsDNA Microcircle Via a Kissing Loop Intermediate

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 3017
Author(s):  
Alberto Mills ◽  
Federico Gago
Keyword(s):  
Model Building ◽  
Three Dimensional ◽  
3D Models ◽  
Base Pairs ◽  
T4 Dna Ligase ◽  
Double Stranded Dna ◽  
Explicit Solvent ◽  
Dynamics Simulations ◽  
Enzyme Recognition ◽  
Kissing Loop

The experimental construction of a double-stranded DNA microcircle of only 42 base pairs entailed a great deal of ingenuity and hard work. However, figuring out the three-dimensional structures of intermediates and the final product can be particularly baffling. Using a combination of model building and unrestrained molecular dynamics simulations in explicit solvent we have characterized the different DNA structures involved along the process. Our 3D models of the single-stranded DNA molecules provide atomic insight into the recognition event that must take place for the DNA bases in the cohesive tail of the hairpin to pair with their complementary bases in the single-stranded loops of the dumbbell. We propose that a kissing loop involving six base pairs makes up the core of the nascent dsDNA microcircle. We also suggest a feasible pathway for the hybridization of the remaining complementary bases and characterize the final covalently closed dsDNA microcircle as possessing two well-defined U-turns. Additional models of the pre-ligation complex of T4 DNA ligase with the DNA dumbbell and the post-ligation pre-release complex involving the same enzyme and the covalently closed DNA microcircle are shown to be compatible with enzyme recognition and gap ligation.

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.

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