B-DNA's B<sub>I</sub> → B<sub>II</sub> Conformer Substate Dynamics Is Coupled with Water Migration

Winger, Rudolf H.; Liedl, Klaus R.; Rüdisser, Simon; Pichler, Arthur; Hallbrucker, Andreas; Mayer, Erwin

doi:10.1021/jp983005f

Cited by 58 publications

(103 citation statements)

References 94 publications

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“…As previously pointed out, 3,8,44,45 our simulations show that CpA.TpG, GpG, GpA, and to a smaller extent, GpC and ApA, backbones have higher propensities for BII conformers. A majority of these dinucleotides (33 on a total of 48) shows significant BII conformations on one strand (Ͼ10%), associated with a facing strand with few BII conformers (Ͻ 10%).…”

Section: Bii Conformations In Two Biological Dna Targetssupporting

confidence: 78%

DNA fine structure and dynamics in crystals and in solution: The impact of BI/BII backbone conformations

2003

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Sugar-phosphate backbone conformations are an important structural element for a complete understanding of specific recognition in nucleic acid-protein interactions. They can be involved both in early stages of target discrimination and in structural adaptation upon binding. In the first part of this study, we have analyzed high-resolution structures of double-stranded B-DNA either isolated or bound to proteins, and explored the impact of both the standard BI and the unusual BII phosphate backbone conformations on neighboring sugar puckers and on selected helical parameters. Correlations are found to be similar for free and bound DNA, and in both categories, the possible facing backbone conformations (BI.BI, BI.BII, and BII.BII) define well-characterized substates in the B-DNA conformational space. Notably, BII.BII steps are characterized by specific, and sequence-independent, structural effects involving reduced standard deviations for almost all conformational parameters. In the second part of this work, we analyze four 10 ns molecular dynamics simulations in explicit solvent on the DNA targets of NF-kappaB and bovine papillomavirus E2 proteins, highlighting the multiplicity of backbone dynamical behavior. These results show sequence effects on the percentages of BI and BII conformers, the preferential state of facing backbones, the occurrence of coupled transitions. The backbone states can consequently be seen as a mechanism for transmitting information from the bases to the phosphate groups and thus for modulating the overall structural properties of the target DNA.

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Section: Bii Conformations In Two Biological Dna Targetssupporting

confidence: 78%

DNA fine structure and dynamics in crystals and in solution: The impact of BI/BII backbone conformations

2003

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“…3). This result opposes the report that the B II conformation does not occur at the pyrimidine͞pyrimidine base step (19,20). The B II conformation is formed to overcome the energy barrier due to the destacking of adjacent bases.…”

Section: Methodscontrasting

confidence: 98%

“…This result can be attributed to the DNA-conformational variations at the T 5Ј ͞C 4Ј that can no longer accommodate water molecules. This feature is consistent with the studies on EcoRI endonuclease, which indicates the B II conformation to be associated with the decrease of water content (20). The subsequent displacement of nucleotides in ETS-GGAG also results in disruption of hydrogen bonding of Arg-394 to G 1 nucleotide after 2,000 ps of dynamics (5).…”

Section: °(Transsupporting

confidence: 90%

Conformations and dynamics of Ets-1 ETS domain–DNA complexes

Reddy

Obika

Bruice

2003

Proc. Natl. Acad. Sci. U.S.A.

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Molecular dynamics studies have been performed for 3.5 ns on the ETS domain of Ets-1 transcription factor bound to the 14-bp DNA, d(AGTGCCGGAAATGT), comprising the core sequence of high-affinity (GGAA), ETS-GGAA. In like manner, molecular dynamics simulations have been carried out for 3.9 ns on the mutant low-affinity core sequence, GGAG (ETS-GGAG). Analyses of the DNA backbone of ETS-GGAG show conformational interconversions from BI to BII substates. Also, crank shaft motions are noticed at the mutated nucleotide base pair step after 1,500 ps of dynamics. The corresponding nucleotide of ETS-GGAA is characteristic of a BI conformation and no crank shaft motions are observed. The single mutation of ETS-GGAA to ETS-GGAG also results in variations of helical parameters and solvent-accessible surface area around the major and minor grooves of the DNA. The presence of water contacts during the entire simulation proximal to the fourth base pair step of core DNA sequence is a characteristic feature of ETS-GGAA. Such waters are more mobile in ETS-GGAG at 100 ps and distant after 1,500 ps. Anticorrelated motions between certain amino acids of Ets-1 protein are predominant in ETS-GGAA but less so or absent in the mutant. These motions are reflected in the flexibility of amino acid residues of the protein backbone. We consider that these conformational features and water contacts are involved in stabilizing the hydrogen bond interactions between helix-3 residues of Ets-1 and DNA during the transcription process. The Ets protein family of transcription factors includes species interacting with various genes that code for transcriptional activators and inhibitors involved in cell proliferation and differentiation (1, 2). The regulation of the initiation of gene transcription arises from the combined activity of different transcriptional regulators (2, 3). Ets family members found in species from invertebrates to humans share a conserved sequence of 85 amino acids, named the ETS domain. The ETS domain folds into a winged helix-turn-helix motif and binds to a consensus DNA sequence centered on the core GGAA motif, named the Ets-binding site. The sequences flanking this core motif (in the major groove) are variable and characterize the specificity of binding of the Ets transcription factor. Ets proteins have also been implicated in several types of cancer and other human diseases (4). Detailed conformational preferences that influence the sequence specificity of Ets proteins are essential for the design of anticancer drugs.The high-affinity DNA contains the GGAA core sequence, ETS-GGAA (Fig. 1). The low-affinity DNA is the single-base-pair mutant, ETS-GGAG. Recently we reported molecular dynamics (MD) studies (5) dealing with the binding of the ETS domain of Ets-1 protein to the high-and low-affinity 14-bp DNA structures. We have observed that the most conserved residues Arg-391, Arg-394, along with Tyr-395 of Ets-1, jointly contribute to recognize the GGAA or GGAG core DNA sequences (5). The differential hydrogen bond interact...

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“…To determine BI/BII equilibrium in B-DNA, proton and Phosphate NMR experiments [4][5][6][7] , Molecular Dynamics (MD) simulations [8][9][10] , and data mining of crystal structures from databases [11][12][13] have being historically used as the preferred methods. Following initial observations based on crystal structures showing that BI/BII transitions were associated with base destacking and minor groove widening 14,15 , computer MD simulations have shed light on the influence of water and ion dynamics on the propensity of BI/BII states 8,9,16,17 .…”

Section: Introductionmentioning

confidence: 99%

The Role of Unconventional Hydrogen Bonds in Determining BII Propensities in B-DNA

Balaceanu

Pasi

Dans

et al. 2016

J. Phys. Chem. Lett.

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An accurate understanding of DNA backbone transitions is likely to be the key for elucidating the puzzle of the intricate sequence-dependent mechanical properties that govern most of the biologically relevant functions of the double helix. One factor believed to be important in indirect recognition within protein-DNA complexes is the combined effect of two DNA backbone torsions (ε and ζ) which give rise to the well-known BI/BII conformational equilibrium. In this work we explain the sequence dependent BII propensity observed in RpY steps (R = purine; Y = pyrimidine) at the tetranucleotide level with the help of a previously undetected C-H···O contact between atoms belonging to adjacent bases. Our results are supported by extensive multi-microsecond molecular dynamics simulations from the Ascona B-DNA Consortium, high-level quantum mechanical calculations, and data mining of the experimental structures deposited in the Protein Data Bank.

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B-DNA's B_I → B_II Conformer Substate Dynamics Is Coupled with Water Migration

Cited by 58 publications

References 94 publications

DNA fine structure and dynamics in crystals and in solution: The impact of BI/BII backbone conformations

DNA fine structure and dynamics in crystals and in solution: The impact of BI/BII backbone conformations

Conformations and dynamics of Ets-1 ETS domain–DNA complexes

The Role of Unconventional Hydrogen Bonds in Determining BII Propensities in B-DNA

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B-DNA's BI → BII Conformer Substate Dynamics Is Coupled with Water Migration

Cited by 58 publications

References 94 publications

DNA fine structure and dynamics in crystals and in solution: The impact of BI/BII backbone conformations

DNA fine structure and dynamics in crystals and in solution: The impact of BI/BII backbone conformations

Conformations and dynamics of Ets-1 ETS domain–DNA complexes

The Role of Unconventional Hydrogen Bonds in Determining BII Propensities in B-DNA

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Product

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B-DNA's B_I → B_II Conformer Substate Dynamics Is Coupled with Water Migration