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Indirect readout: detection of optimized subsequences and calculation of relative binding affinities using different DNA elastic potentials.

Becker NB, Wolff L, Everaers R - Nucleic Acids Res. (2006)

Bottom Line: In agreement with known results we find that indirect readout dominates at the central, non-contacted bases of the binding site.Their quantitative comparison with experimental data allows for a critical evaluation of DNA elastic potentials and of the correspondence between crystal and solution structures.The software written for the presented analysis is included as Supplementary Data.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck-Institut für Physik komplexer Systeme, Nöthnitzer Strasse 38, 01187 Dresden, Germany. nbecker@pks.mpg.de

ABSTRACT
Essential biological processes require that proteins bind to a set of specific DNA sites with tuned relative affinities. We focus on the indirect readout mechanism and discuss its theoretical description in relation to the present understanding of DNA elasticity on the rigid base pair level. Combining existing parametrizations of elastic potentials for DNA, we derive elastic free energies directly related to competitive binding experiments, and propose a computationally inexpensive local marker for elastically optimized subsequences in protein-DNA co-crystals. We test our approach in an application to the bacteriophage 434 repressor. In agreement with known results we find that indirect readout dominates at the central, non-contacted bases of the binding site. Elastic optimization involves all deformation modes and is mainly due to the adapted equilibrium structure of the operator, while sequence-dependent elasticity plays a minor role. These qualitative observations are robust with respect to current parametrization uncertainties. Predictions for relative affinities mediated by indirect readout depend sensitively on the chosen parametrization. Their quantitative comparison with experimental data allows for a critical evaluation of DNA elastic potentials and of the correspondence between crystal and solution structures. The software written for the presented analysis is included as Supplementary Data.

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Related in: MedlinePlus

Similarity to elastic consensus for native subsequences in the OR complexes. Information (gray) and scaled native probability (green) are shown for 1, 2 and 4 bp subsequences, from top to bottom.
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fig6: Similarity to elastic consensus for native subsequences in the OR complexes. Information (gray) and scaled native probability (green) are shown for 1, 2 and 4 bp subsequences, from top to bottom.

Mentions: It has been pointed out (29) that different distributions pi(b) contain varying amounts of information. For example, a position i at which all bases are equally probable has no information and should be considered as carrying no elastic specificity. Extending this to the case of k + 1 bases, we need to calculate the entropy of the distribution ,21Σi,i+k=−∑σ′′pi,i+k(σ′)ln[pi,i+k(σ′)]≤(k+1)ln4.A measure for the information content of the distribution that ranges from 0 to 1 is given by . An extension of a sequence logo (29) for length k + 1 subsequences can then be constructed by plotting the relative frequency of each subsequence, scaled with the information content, along the complex. For k > 0, the subsequences overlap, so the usual letter scaling notation cannot be used. However, the most interesting information can be shown by plotting for native subsequences only, see Figure 6 below. Such a plot shows directly how well the native sequence coincides with an elastic consensus sequence, and gives a local marker for which significantly nonzero values point to elastic specificity. Again, since the subsequence length of interest is usually just a few base pairs, computation is cheap.


Indirect readout: detection of optimized subsequences and calculation of relative binding affinities using different DNA elastic potentials.

Becker NB, Wolff L, Everaers R - Nucleic Acids Res. (2006)

Similarity to elastic consensus for native subsequences in the OR complexes. Information (gray) and scaled native probability (green) are shown for 1, 2 and 4 bp subsequences, from top to bottom.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1636474&req=5

fig6: Similarity to elastic consensus for native subsequences in the OR complexes. Information (gray) and scaled native probability (green) are shown for 1, 2 and 4 bp subsequences, from top to bottom.
Mentions: It has been pointed out (29) that different distributions pi(b) contain varying amounts of information. For example, a position i at which all bases are equally probable has no information and should be considered as carrying no elastic specificity. Extending this to the case of k + 1 bases, we need to calculate the entropy of the distribution ,21Σi,i+k=−∑σ′′pi,i+k(σ′)ln[pi,i+k(σ′)]≤(k+1)ln4.A measure for the information content of the distribution that ranges from 0 to 1 is given by . An extension of a sequence logo (29) for length k + 1 subsequences can then be constructed by plotting the relative frequency of each subsequence, scaled with the information content, along the complex. For k > 0, the subsequences overlap, so the usual letter scaling notation cannot be used. However, the most interesting information can be shown by plotting for native subsequences only, see Figure 6 below. Such a plot shows directly how well the native sequence coincides with an elastic consensus sequence, and gives a local marker for which significantly nonzero values point to elastic specificity. Again, since the subsequence length of interest is usually just a few base pairs, computation is cheap.

Bottom Line: In agreement with known results we find that indirect readout dominates at the central, non-contacted bases of the binding site.Their quantitative comparison with experimental data allows for a critical evaluation of DNA elastic potentials and of the correspondence between crystal and solution structures.The software written for the presented analysis is included as Supplementary Data.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck-Institut für Physik komplexer Systeme, Nöthnitzer Strasse 38, 01187 Dresden, Germany. nbecker@pks.mpg.de

ABSTRACT
Essential biological processes require that proteins bind to a set of specific DNA sites with tuned relative affinities. We focus on the indirect readout mechanism and discuss its theoretical description in relation to the present understanding of DNA elasticity on the rigid base pair level. Combining existing parametrizations of elastic potentials for DNA, we derive elastic free energies directly related to competitive binding experiments, and propose a computationally inexpensive local marker for elastically optimized subsequences in protein-DNA co-crystals. We test our approach in an application to the bacteriophage 434 repressor. In agreement with known results we find that indirect readout dominates at the central, non-contacted bases of the binding site. Elastic optimization involves all deformation modes and is mainly due to the adapted equilibrium structure of the operator, while sequence-dependent elasticity plays a minor role. These qualitative observations are robust with respect to current parametrization uncertainties. Predictions for relative affinities mediated by indirect readout depend sensitively on the chosen parametrization. Their quantitative comparison with experimental data allows for a critical evaluation of DNA elastic potentials and of the correspondence between crystal and solution structures. The software written for the presented analysis is included as Supplementary Data.

Show MeSH
Related in: MedlinePlus