Inclusion of methoxy groups inverts the thermodynamic stabilities of DNA–RNA hybrid duplexes: A molecular dynamics simulation study

Gorle, Suresh

doi:10.1016/j.jmgm.2015.07.009

Cited by 3 publications

(7 citation statements)

References 59 publications

(110 reference statements)

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“…The molecular mechanicsgeneralized Born with surface area (MM-GBSA) method was used to calculate the binding free energies corresponding to the formation of the duplex from individual strands that uses the molecular mechanical energy, solvation energy, and entropy of the system. 39,40…”

Section: ■ Computational Methodsmentioning

confidence: 99%

“…Although NMR experiments provide valuable information about the structures of urea- and formamide-incorporated B-DNA duplexes, the complete characterization of DNA duplexes with urea lesions has been difficult because of the resonance overlap of the signals. , Molecular dynamics (MD) simulations are, in general, very useful for studying the structure, dynamics, and thermodynamic stability of damaged and chemically modified nucleic acid duplexes. − In the study presented here, MD simulations have been performed on the B-DNA duplexes with a urea lesion opposite four nucleobases, adenine (A), thymine (T), guanine (G), and cytosine (C), in Watson–Crick (WC), Hoogsteen, and sugar edge interactions. Analyses of the MD trajectories suggest that the urea lesions prefer to form WC-like hydrogen bond interactions with the nucleobases, especially purines, and can potentially mimic the nucleobases in B-DNA duplexes.…”

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confidence: 99%

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Urea Mimics Nucleobases by Preserving the Helical Integrity of B-DNA Duplexes via Hydrogen Bonding and Stacking Interactions

2016

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Urea lesions are formed in DNA because of free radical damage of the thymine base, and their occurrence in DNA blocks DNA polymerases, which has deleterious consequences. Recently, it has been shown that urea is capable of forming hydrogen bonding and stacking interactions with nucleobases, which are responsible for the unfolding of RNA in aqueous urea. Base pairing and stacking are inherent properties of nucleobases; because urea is able to form both, this study attempts to investigate if urea can mimic nucleobases in the context of nucleic acid structures by examining the effect of introducing urea lesions complementary to the four different nucleobases on the overall helical integrity of B-DNA duplexes and their thermodynamic stabilities using molecular dynamics (MD) simulations. The MD simulations resulted in stable duplexes without significant changes in the global B-DNA conformation. The urea lesions occupy intrahelical positions by forming hydrogen bonds with nitrogenous nucleobases, in agreement with experimental results. Furthermore, these urea lesions form hydrogen bonding and stacking interactions with other nucleobases of the same and partner strands, analogous to nucleobases in typical B-DNA duplexes. Direct hydrogen bond interactions are observed for the urea-purine pairs within DNA duplexes, whereas two different modes of pairing, namely, direct hydrogen bonds and water-mediated hydrogen bonds, are observed for the urea-pyrimidine pairs. The latter explains the complexities involved in interpreting the experimental nuclear magnetic resonance data reported previously. Binding free energy calculations were further performed to confirm the thermodynamic stability of the urea-incorporated DNA duplexes with respect to pure duplexes. This study suggests that urea mimics nucleobases by pairing opposite all four nucleobases and maintains the overall structure of the B-DNA duplexes.

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Section: ■ Computational Methodsmentioning

confidence: 99%

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confidence: 99%

Urea Mimics Nucleobases by Preserving the Helical Integrity of B-DNA Duplexes via Hydrogen Bonding and Stacking Interactions

2016

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“…The images of structures depicted in this work were rendered using VMD . All the stacking interactions corresponding to nucleobases have been calculated in a similar way as mentioned elsewhere. − Principal component analysis (PCA) has been performed on the combined trajectory of all the trajectories corresponding to holo and apo systems by considering all the atoms of the nucleotides. The covariance matrix of the x , y , and z coordinates of all the atoms was obtained from each snapshot of the combined trajectory after aligning the non-hydrogen atoms of the SAM-III structure.…”

Section: Materials and Methodsmentioning

confidence: 99%

Ligand-Induced Stabilization of a Duplex-like Architecture Is Crucial for the Switching Mechanism of the SAM-III Riboswitch

2016

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Riboswitches are structured RNA motifs that control gene expression by sensing the concentrations of specific metabolites and make up a promising new class of antibiotic targets. S-Adenosylmethionine (SAM)-III riboswitch, mainly found in lactic acid bacteria, is involved in regulating methionine and SAM biosynthetic pathways. SAM-III riboswitch regulates the gene expression by switching the translation process on and off with respect to the absence and presence of the SAM ligand, respectively. In this study, an attempt is made to understand the key conformational transitions involved in ligand binding using atomistic molecular dynamics (MD) simulations performed in an explicit solvent environment. G26 is found to recognize the SAM ligand by forming hydrogen bonds, whereas the absence of the ligand leads to opening of the binding pocket. Consistent with experimental results, the absence of the SAM ligand weakens the base pairing interactions between the nucleobases that are part of the Shine-Dalgarno (SD) and anti-Shine-Dalgarno (aSD) sequences, which in turn facilitates recognition of the SD sequence by ribosomes. Detailed analysis reveals that a duplex-like structure formed by nucleotides from different parts of the RNA and the adenine base of the ligand is crucial for the stability of the completely folded state in the presence of the ligand. Previous experimental studies have shown that the SAM-III riboswitch exists in equilibrium between the unfolded and partially folded states in the absence of the ligand, which completely folds upon binding of the ligand. Comparison of the results presented here to the available experimental data indicates the structures obtained using the MD simulations resemble the partially folded state. Thus, this study provides a detailed understanding of the fully and partially folded structures of the SAM-III riboswitch in the presence and absence of the ligand, respectively. This study hypothesizes a dual role for the SAM ligand, which facilitates conformational switching between partially and fully folded states by forming a stable duplex-like structure and strengthening the interactions between SD and aSD nucleotides.

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“…MD methods are used to analyze the structure and hybridization properties of not only native oligonucleotides but also their analogs and derivatives to establish their possible spatial structure, the effect of modifications on the thermal stability of complementary complexes, and the reasons for the observed physicochemical and molecular-biological effects. The energy of the formation of modified complexes was calculated for locked NA (LNA) [59], peptidyl NA (PNA) [35], 2'-O-Me RNA [34], glycine-morpholino analogs [32], and phosphoryl guanidine oligonucleotides [33]. Researchers used various approaches including the most common MMPB(GB)SA method, which we °Δ 37 G also implemented.…”

Section: Energy Of Formation Of Dna/rna Complexesmentioning

confidence: 99%

“…These methods of estimating the energy of intermolecular interactions are widely used when studying the interactions of biopolymers with small molecules, e.g., in molecular biological studies [28] or the development of new drugs [29]. The successful application of these approaches has also been demonstrated for calculation of the energy of complex formation with DNA and RNA of both native [30,31] and chemically modified oligonucleotides [32][33][34][35][36]. However, in the latter case, the research is not systematic; it is rather an illustration of the possibilities of the methods.…”

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Calculation of Energy for RNA/RNA and DNA/RNA Duplex Formation by Molecular Dynamics Simulation

2021

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The development of approaches for predictive calculation of hybridization properties of various nucleic acid (NA) derivatives is the basis for the rational design of the NA-based constructs. Modern advances in computer modeling methods provide the feasibility of these calculations. We have analyzed the possibility of calculating the energy of DNA/RNA and RNA/RNA duplex formation using representative sets of complexes (65 and 75 complexes, respectively). We used the classical molecular dynamics (MD) method, the MMPBSA or MMGBSA approaches to calculate the enthalpy (ΔH°) component, and the quasi-harmonic approximation (Q-Harm) or the normal mode analysis (NMA) methods to calculate the entropy (ΔS°) contribution to the Gibbs energy ($$\Delta G_{{37}}^{^\circ }$$ ) of the NA complex formation. We have found that the MMGBSA method in the analysis of the MD trajectory of only the NA duplex and the empirical linear approximation allow calculation of the enthalpy of formation of the DNA, RNA, and hybrid duplexes of various lengths and GC content with an accuracy of 8.6%. Within each type of complex, the combination of rather efficient MMGBSA and Q-Harm approaches being applied to the trajectory of only the bimolecular complex makes it possible to calculate the $$\Delta G_{{37}}^{^\circ }$$ of the duplex formation with an error value of 10%. The high accuracy of predictive calculation for different types of natural complexes (DNA/RNA, DNA/RNA, and RNA/RNA) indicates the possibility of extending the considered approach to analogs and derivatives of nucleic acids, which gives a fundamental opportunity in the future to perform rational design of new types of NA-targeted sequence-specific compounds.

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Inclusion of methoxy groups inverts the thermodynamic stabilities of DNA–RNA hybrid duplexes: A molecular dynamics simulation study

Cited by 3 publications

References 59 publications

Urea Mimics Nucleobases by Preserving the Helical Integrity of B-DNA Duplexes via Hydrogen Bonding and Stacking Interactions

Urea Mimics Nucleobases by Preserving the Helical Integrity of B-DNA Duplexes via Hydrogen Bonding and Stacking Interactions

Ligand-Induced Stabilization of a Duplex-like Architecture Is Crucial for the Switching Mechanism of the SAM-III Riboswitch

Calculation of Energy for RNA/RNA and DNA/RNA Duplex Formation by Molecular Dynamics Simulation

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