Limits...
Energetics of protein-DNA interactions.

Donald JE, Chen WW, Shakhnovich EI - Nucleic Acids Res. (2007)

Bottom Line: Protein-DNA interactions are vital for many processes in living cells, especially transcriptional regulation and DNA modification.To further our understanding of these important processes on the microscopic level, it is necessary that theoretical models describe the macromolecular interaction energetics accurately.In addition to carrying out the comparison, we present two important theoretical models developed initially in protein folding that have not yet been tried on protein-DNA interactions.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St. Cambridge, MA 02138, USA. jdonald@fas.harvard.edu

ABSTRACT
Protein-DNA interactions are vital for many processes in living cells, especially transcriptional regulation and DNA modification. To further our understanding of these important processes on the microscopic level, it is necessary that theoretical models describe the macromolecular interaction energetics accurately. While several methods have been proposed, there has not been a careful comparison of how well the different methods are able to predict biologically important quantities such as the correct DNA binding sequence, total binding free energy and free energy changes caused by DNA mutation. In addition to carrying out the comparison, we present two important theoretical models developed initially in protein folding that have not yet been tried on protein-DNA interactions. In the process, we find that the results of these knowledge-based potentials show a strong dependence on the interaction distance and the derivation method. Finally, we present a knowledge-based potential that gives comparable or superior results to the best of the other methods, including the molecular mechanics force field AMBER99.

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Database dependence of the quasichemical potential with multiple distance bins (0–7 Å). The dashed line represents the final value when the full training set is used. (A) Results for the specificity test on the testing set. Smaller values represent more accurate predictions. (B) Results for the ΔΔG test. The ΔΔG test measures the correlation between predicted and experimentally determined free energy changes when DNA bases are mutated. Because the ΔΔG test measures the correlation with experiment, larger values show better predictions.
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Figure 3: Database dependence of the quasichemical potential with multiple distance bins (0–7 Å). The dashed line represents the final value when the full training set is used. (A) Results for the specificity test on the testing set. Smaller values represent more accurate predictions. (B) Results for the ΔΔG test. The ΔΔG test measures the correlation between predicted and experimentally determined free energy changes when DNA bases are mutated. Because the ΔΔG test measures the correlation with experiment, larger values show better predictions.

Mentions: As shown in Figure 3, the quasichemical potential appears to be approaching, but perhaps not to have reached, a limiting value. Extrapolating these trends to when more protein–DNA structures are known, the prediction of ΔΔG changes and the correct DNA-binding sequence may show a modest improvement as more protein–DNA crystal structures are determined.Figure 3.


Energetics of protein-DNA interactions.

Donald JE, Chen WW, Shakhnovich EI - Nucleic Acids Res. (2007)

Database dependence of the quasichemical potential with multiple distance bins (0–7 Å). The dashed line represents the final value when the full training set is used. (A) Results for the specificity test on the testing set. Smaller values represent more accurate predictions. (B) Results for the ΔΔG test. The ΔΔG test measures the correlation between predicted and experimentally determined free energy changes when DNA bases are mutated. Because the ΔΔG test measures the correlation with experiment, larger values show better predictions.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1851630&req=5

Figure 3: Database dependence of the quasichemical potential with multiple distance bins (0–7 Å). The dashed line represents the final value when the full training set is used. (A) Results for the specificity test on the testing set. Smaller values represent more accurate predictions. (B) Results for the ΔΔG test. The ΔΔG test measures the correlation between predicted and experimentally determined free energy changes when DNA bases are mutated. Because the ΔΔG test measures the correlation with experiment, larger values show better predictions.
Mentions: As shown in Figure 3, the quasichemical potential appears to be approaching, but perhaps not to have reached, a limiting value. Extrapolating these trends to when more protein–DNA structures are known, the prediction of ΔΔG changes and the correct DNA-binding sequence may show a modest improvement as more protein–DNA crystal structures are determined.Figure 3.

Bottom Line: Protein-DNA interactions are vital for many processes in living cells, especially transcriptional regulation and DNA modification.To further our understanding of these important processes on the microscopic level, it is necessary that theoretical models describe the macromolecular interaction energetics accurately.In addition to carrying out the comparison, we present two important theoretical models developed initially in protein folding that have not yet been tried on protein-DNA interactions.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St. Cambridge, MA 02138, USA. jdonald@fas.harvard.edu

ABSTRACT
Protein-DNA interactions are vital for many processes in living cells, especially transcriptional regulation and DNA modification. To further our understanding of these important processes on the microscopic level, it is necessary that theoretical models describe the macromolecular interaction energetics accurately. While several methods have been proposed, there has not been a careful comparison of how well the different methods are able to predict biologically important quantities such as the correct DNA binding sequence, total binding free energy and free energy changes caused by DNA mutation. In addition to carrying out the comparison, we present two important theoretical models developed initially in protein folding that have not yet been tried on protein-DNA interactions. In the process, we find that the results of these knowledge-based potentials show a strong dependence on the interaction distance and the derivation method. Finally, we present a knowledge-based potential that gives comparable or superior results to the best of the other methods, including the molecular mechanics force field AMBER99.

Show MeSH
Related in: MedlinePlus