DNA sequence and structure: direct and indirect recognition in
protein-DNA binding

Steffen, Nicholas R.; Murphy, Scott D.; Tolleri, Lorenzo; Hatfield, G. Wesley; Lathrop, Richard H.

doi:10.1093/bioinformatics/18.suppl_1.s22

Cited by 60 publications

(54 citation statements)

References 17 publications

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“…In this study, we have shown that IHF recognizes pre-formed conformational characteristics of the consensus DNA sequence. At all other sites, relative affinity is defined by the conformational freedom of individual base pair steps to adopt the DNA structure of the bound IHF-DNA complex (21,22).…”

Section: Discussionmentioning

confidence: 99%

“…The 8-bp flanking sequences are from the HЈ IHF-binding site; these were held constant. Only the central 34 bp were considered in calculation of deformation energy, as described by Steffan et al (21,22).…”

Section: Methodsmentioning

confidence: 99%

“…An advantage is that this yields a single set of internally consistent results at a standard condition, thus removing a large source of expected variation. In addition, it addresses an inherent limitation of the natural sequences, which is a relatively narrow range of deformation energy as compared with the entire E. coli genome (21). Sequences designed in this manner were compared with a set of control sequences that feature variation both in the conservation of consensus elements and also in nonconserved regions to generate a broad range of deformation energies.…”

Section: Analysis Of Naturally Occurring Ihf-binding Sites-mentioning

confidence: 99%

“…DNA sequences were threaded onto the structure of the HЈ site in the bound complex (17), and the energy difference between these DNA sequences in the bound conformation and the same sequences in their native, unbound conformations was estimated using the harmonic conformational potentials of Olson et al (20). Results indicated lower average deformation energy and a narrower distribution for known IHF sites as compared with either sequences selected at random from the E. coli genome, or generated as random sequences matching the E. coli base composition (21). Deformation energy calculated in this manner was used to seed classifiers that could be trained to identify IHF-binding sites (22).…”

mentioning

confidence: 99%

“…An additional set of E. coli genomic sequences was also analyzed. These sequences were selected as putative, but as yet uncharacterized, IHF regulatory sites based on classifiers described previously (21,22,24). Like the control sequences and other natural IHF regulatory sites, these exhibit variation in both consensus elements and nonconserved sequences.…”

mentioning

confidence: 99%

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Indirect Recognition in Sequence-specific DNA Binding by Escherichia coli Integration Host Factor

Aeling

Opel

Steffen

et al. 2006

Journal of Biological Chemistry

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Integration host factor (IHF) is a bacterial histone-like protein whose primary biological role is to condense the bacterial nucleoid and to constrain DNA supercoils. It does so by binding in a sequence-independent manner throughout the genome. However, unlike other structurally related bacterial histone-like proteins, IHF has evolved a sequence-dependent, high affinity DNA-binding motif. The high affinity binding sites are important for the regulation of a wide range of cellular processes. A remarkable feature of IHF is that it employs an indirect readout mechanism to bind and wrap DNA at both the nonspecific and high affinity (sequence-dependent) DNA sites. In this study we assessed the contributions of pre-formed and protein-induced DNA conformations to the energetics of IHF binding. Binding energies determined experimentally were compared with energies predicted for the IHF-induced deformation of the DNA helix (DNA deformation energy) in the IHF-DNA complex. Combinatorial sets of de novo DNA sequences were designed to systematically evaluate the influence of sequence-dependent structural characteristics of the conserved IHF recognition elements of the consensus DNA sequence. We show that IHF recognizes pre-formed conformational characteristics of the consensus DNA sequence at high affinity sites, whereas at all other sites relative affinity is determined by the deformational energy required for nearest-neighbor base pairs to adopt the DNA structure of the bound DNA-IHF complex.Site-specific DNA binding by regulatory proteins is a feature of the regulatory processes that maintain, expand, and express genetic information such as replication, recombination, transposition, and transcription. The chemical and physical mechanisms that underlie sequence-specific recognition of regulatory elements by cognate DNA-binding proteins are typically classified as direct versus indirect readout. The former refers primarily to hydrogen bonds between proteins and the unique extra-cyclic substituents at C-4 of pyrimidines, C-6 of purines, and N-7 of purines. These groups provide a base pair-specific pattern of hydrogen bond donors and acceptors in the major groove of DNA that can be directly read by a complementary pattern of amino acid side chain donors and acceptors. Indirect readout refers to recognition of aspects of DNA structure such as intrinsic curvature, topology of major and minor grooves, ordered water structures, local geometry of backbone phosphates, and flexibility or deformability. Because both the local DNA structure and energy to deform DNA are themselves intrinsic sequence-dependent properties, the conserved sequences that distinguish binding sites necessarily include contributions from both direct and indirect mechanisms. Consequently, although the contribution from indirect mechanisms is expected to be significant in protein-DNA complexes that feature substantial DNA deformation, it has proven difficult to evaluate these contributions quantitatively. A protein that relies exclusively, or primarily, on indir...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Analysis Of Naturally Occurring Ihf-binding Sites-mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Indirect Recognition in Sequence-specific DNA Binding by Escherichia coli Integration Host Factor

Aeling

Opel

Steffen

et al. 2006

Journal of Biological Chemistry

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Toward an atomistic model for predicting transcription‐factor binding sites

Endres

Schulthess

Wingreen³

2004

Proteins

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Identifying the specific DNA-binding sites of transcription-factor proteins is essential to understanding the regulation of gene expression in the cell. Bioinformatics approaches are fast compared to experiments, but require prior knowledge of multiple binding sites for each protein. Here, we present an atomistic force-field method to predict binding sites based only on the X-ray structure of a related bound complex. Specific flexible contacts between the protein and DNA are modeled by a library of amino acid side-chain rotamers. Using the example of the mouse transcription factor, Zif268, a well-studied zinc-finger protein, we show that the protein sequence alone, without the detailed experimental structure, gives a strong bias toward the consensus binding site.

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ProtNA‐ASA: Protein‐nucleic acid structural database with information on accessible surface area

Tkachenko

Boryskina

Shestopalova

et al. 2009

Int J of Quantum Chemistry

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The article describes a new database (ProtNA-ASA), which combines the data on conformational parameters of nucleic acids and calculations of the accessible surface area (ASA) of nucleic acid atoms in protein-DNA/RNA complexes. As for October 2008, the database contains 214 DNA-protein and 28 RNA-protein nonhomologous complexes. The database provides structural parameters that describe local geometry of base pairs and base-pair steps as well as backbone torsion angles. Additionally, total ASA of DNA/RNA atoms and the accessible area of atoms in the minor and major grooves are calculated. ProtNA-ASA database facilitates studying the relationship between the DNA/RNA conformation and availability of atoms for contact with proteins either in major or in minor groove for different nucleotides. Such an analysis is important for understanding the principles of molecular recognition including indirect sequence readout. The database is publicly available for use at

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DNA sequence and structure: direct and indirect recognition in protein-DNA binding

Cited by 60 publications

References 17 publications

Indirect Recognition in Sequence-specific DNA Binding by Escherichia coli Integration Host Factor

Indirect Recognition in Sequence-specific DNA Binding by Escherichia coli Integration Host Factor

Toward an atomistic model for predicting transcription‐factor binding sites

ProtNA‐ASA: Protein‐nucleic acid structural database with information on accessible surface area

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