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Detecting cis-regulatory binding sites for cooperatively binding proteins.

van Oeffelen L, Cornelis P, Van Delm W, De Ridder F, De Moor B, Moreau Y - Nucleic Acids Res. (2008)

Bottom Line: As the best way to detect cis-regulatory modules is the way in which the proteins recognize them, we developed a new scoring method that utilizes the underlying physical binding model.The heterotypic cooperative binding model requires one more parameter per cooperatively binding protein, which is the concentration multiplied by the partition function of this protein.In a case study on the bacterial ferric uptake regulator, we show that our scoring method for homotypic cooperatively binding proteins significantly outperforms other PWM-based methods where biophysical cooperativity is not taken into account.

View Article: PubMed Central - PubMed

Affiliation: Department of Electrical Engineering, ESAT-SCD, Katholieke Universiteit Leuven, Kasteelpark Arenberg 10, 3001 Leuven, Belgium. Liesbeth.vanOeffelen@esat.kuleuven.be

ABSTRACT
Several methods are available to predict cis-regulatory modules in DNA based on position weight matrices. However, the performance of these methods generally depends on a number of additional parameters that cannot be derived from sequences and are difficult to estimate because they have no physical meaning. As the best way to detect cis-regulatory modules is the way in which the proteins recognize them, we developed a new scoring method that utilizes the underlying physical binding model. This method requires no additional parameter to account for multiple binding sites; and the only necessary parameters to model homotypic cooperative interactions are the distances between adjacent protein binding sites in basepairs, and the corresponding cooperative binding constants. The heterotypic cooperative binding model requires one more parameter per cooperatively binding protein, which is the concentration multiplied by the partition function of this protein. In a case study on the bacterial ferric uptake regulator, we show that our scoring method for homotypic cooperatively binding proteins significantly outperforms other PWM-based methods where biophysical cooperativity is not taken into account.

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Performance of the cooperative binding model as a function ΔGcoop,6. The area under the TP versus FP curve is shown as a function ofΔGcoop,6 for FP < 5 and FP < 10.
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Figure 3: Performance of the cooperative binding model as a function ΔGcoop,6. The area under the TP versus FP curve is shown as a function ofΔGcoop,6 for FP < 5 and FP < 10.

Mentions: Figure 3 shows the performance of the cooperative binding model for several values of within a realistic range. The area under the FP versus TP curve is plotted for and to make sure that the trend does not depend too much on the considered number of false positives. From this figure, it can immediately be seen that the cooperative binding model explains the microarray data better than the multiple binding sites model: the curves reach a minimum for . Furthermore, the trend corresponds well to our expectations. As long as the estimated is smaller than the true value, we expect that the performance of the method increases with . When the becomes greater than the true value, we anticipate that the performance saturates because a sequence of twice the binding site length does not occur by chance; otherwise the performance would decrease. Only when exceeds the binding energy of a single protein by a few orders of magnitude, the proteins will not be able to discriminate sites in the DNA well anymore since protein–protein recognition will dominate protein–DNA recognition. This results in a performance drop at kcal/mol (this is not shown in Figure 3 for scaling reasons).Figure 3.


Detecting cis-regulatory binding sites for cooperatively binding proteins.

van Oeffelen L, Cornelis P, Van Delm W, De Ridder F, De Moor B, Moreau Y - Nucleic Acids Res. (2008)

Performance of the cooperative binding model as a function ΔGcoop,6. The area under the TP versus FP curve is shown as a function ofΔGcoop,6 for FP < 5 and FP < 10.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2377448&req=5

Figure 3: Performance of the cooperative binding model as a function ΔGcoop,6. The area under the TP versus FP curve is shown as a function ofΔGcoop,6 for FP < 5 and FP < 10.
Mentions: Figure 3 shows the performance of the cooperative binding model for several values of within a realistic range. The area under the FP versus TP curve is plotted for and to make sure that the trend does not depend too much on the considered number of false positives. From this figure, it can immediately be seen that the cooperative binding model explains the microarray data better than the multiple binding sites model: the curves reach a minimum for . Furthermore, the trend corresponds well to our expectations. As long as the estimated is smaller than the true value, we expect that the performance of the method increases with . When the becomes greater than the true value, we anticipate that the performance saturates because a sequence of twice the binding site length does not occur by chance; otherwise the performance would decrease. Only when exceeds the binding energy of a single protein by a few orders of magnitude, the proteins will not be able to discriminate sites in the DNA well anymore since protein–protein recognition will dominate protein–DNA recognition. This results in a performance drop at kcal/mol (this is not shown in Figure 3 for scaling reasons).Figure 3.

Bottom Line: As the best way to detect cis-regulatory modules is the way in which the proteins recognize them, we developed a new scoring method that utilizes the underlying physical binding model.The heterotypic cooperative binding model requires one more parameter per cooperatively binding protein, which is the concentration multiplied by the partition function of this protein.In a case study on the bacterial ferric uptake regulator, we show that our scoring method for homotypic cooperatively binding proteins significantly outperforms other PWM-based methods where biophysical cooperativity is not taken into account.

View Article: PubMed Central - PubMed

Affiliation: Department of Electrical Engineering, ESAT-SCD, Katholieke Universiteit Leuven, Kasteelpark Arenberg 10, 3001 Leuven, Belgium. Liesbeth.vanOeffelen@esat.kuleuven.be

ABSTRACT
Several methods are available to predict cis-regulatory modules in DNA based on position weight matrices. However, the performance of these methods generally depends on a number of additional parameters that cannot be derived from sequences and are difficult to estimate because they have no physical meaning. As the best way to detect cis-regulatory modules is the way in which the proteins recognize them, we developed a new scoring method that utilizes the underlying physical binding model. This method requires no additional parameter to account for multiple binding sites; and the only necessary parameters to model homotypic cooperative interactions are the distances between adjacent protein binding sites in basepairs, and the corresponding cooperative binding constants. The heterotypic cooperative binding model requires one more parameter per cooperatively binding protein, which is the concentration multiplied by the partition function of this protein. In a case study on the bacterial ferric uptake regulator, we show that our scoring method for homotypic cooperatively binding proteins significantly outperforms other PWM-based methods where biophysical cooperativity is not taken into account.

Show MeSH