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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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Elastic energy E and sequence free energy G in the OR2 complex, for all parametrizations used. Full and partial energies are shown, with color coding and offsets as in Figures 2 and 8.
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fig9: Elastic energy E and sequence free energy G in the OR2 complex, for all parametrizations used. Full and partial energies are shown, with color coding and offsets as in Figures 2 and 8.

Mentions: In order to emphasize the features in the energy profiles that are robust with respect to parametrization, we have so far shown mean values and standard deviations of our set of five parametrizations. In the present section we compare these results for different elastic potentials in more detail, using the 434 structures as an example. In Figure 9 we show plots of the elastic energy E and of the sequence free energy G of all mentioned parametrizations, and in addition the crystal ensembles rescaled using effective temperatures for bending only, B′ and P′ (see Materials and Methods).


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)

Elastic energy E and sequence free energy G in the OR2 complex, for all parametrizations used. Full and partial energies are shown, with color coding and offsets as in Figures 2 and 8.
© Copyright Policy
Related In: Results  -  Collection

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

fig9: Elastic energy E and sequence free energy G in the OR2 complex, for all parametrizations used. Full and partial energies are shown, with color coding and offsets as in Figures 2 and 8.
Mentions: In order to emphasize the features in the energy profiles that are robust with respect to parametrization, we have so far shown mean values and standard deviations of our set of five parametrizations. In the present section we compare these results for different elastic potentials in more detail, using the 434 structures as an example. In Figure 9 we show plots of the elastic energy E and of the sequence free energy G of all mentioned parametrizations, and in addition the crystal ensembles rescaled using effective temperatures for bending only, B′ and P′ (see Materials and Methods).

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