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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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Related in: MedlinePlus

Schematic showing the results of a single base pair mutation in our structural representation. A T–A base pair is mutated to the other three possible mutants (G–C, C–G and A–T). The original structure has the PDB code 1a02.
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Figure 1: Schematic showing the results of a single base pair mutation in our structural representation. A T–A base pair is mutated to the other three possible mutants (G–C, C–G and A–T). The original structure has the PDB code 1a02.

Mentions: In order to compare direct readout energy functions alone without considering the different indirect readout models, we only calculate the energies of rigid structures and their computationally mutated complements. The only exception is that structural minimization is used when testing AMBER. Relaxation of the structures would require an accurate and correctly weighted indirect readout energy function. In addition, others have found that using current potentials, relaxation of crystal structures actually decreases the predictive value of these potentials (1,9). Therefore, to change the structure to represent a DNA mutation, we simply replace the crystallized DNA base pair with the new base pair. To replace a base, the original base nitrogen atom bonded to the sugar and the two base carbon atoms bonded to this nitrogen are aligned with the corresponding atoms of the new base. This preserves the sugar base bond and the base planar angle. A representative substitution of base pairs is shown in Figure 1. Standard base structures used for the replacements were taken from 3DNA (27).Figure 1.


Energetics of protein-DNA interactions.

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

Schematic showing the results of a single base pair mutation in our structural representation. A T–A base pair is mutated to the other three possible mutants (G–C, C–G and A–T). The original structure has the PDB code 1a02.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

Figure 1: Schematic showing the results of a single base pair mutation in our structural representation. A T–A base pair is mutated to the other three possible mutants (G–C, C–G and A–T). The original structure has the PDB code 1a02.
Mentions: In order to compare direct readout energy functions alone without considering the different indirect readout models, we only calculate the energies of rigid structures and their computationally mutated complements. The only exception is that structural minimization is used when testing AMBER. Relaxation of the structures would require an accurate and correctly weighted indirect readout energy function. In addition, others have found that using current potentials, relaxation of crystal structures actually decreases the predictive value of these potentials (1,9). Therefore, to change the structure to represent a DNA mutation, we simply replace the crystallized DNA base pair with the new base pair. To replace a base, the original base nitrogen atom bonded to the sugar and the two base carbon atoms bonded to this nitrogen are aligned with the corresponding atoms of the new base. This preserves the sugar base bond and the base planar angle. A representative substitution of base pairs is shown in Figure 1. Standard base structures used for the replacements were taken from 3DNA (27).Figure 1.

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