Identification of DNA-binding protein target sequences by physical effective energy functions. Free energy analysis of lambda repressor-DNA complexes

TL;DR

This study evaluates physical energy functions to predict DNA-binding sites of lambda repressor, demonstrating that physics-based computational methods can effectively complement traditional sequence-based approaches in identifying gene regulatory elements.

Contribution

The paper introduces a protocol using physical effective energy functions for predicting DNA-binding target sequences, validated on lambda repressor-DNA complexes.

Findings

Reproducibility of experimental binding energies decreases with longer molecular dynamics simulations.

The protocol successfully predicts regulatory elements in the lambda genome without prior thermodynamic data.

Physics-based methods provide a valuable complement to sequence-based DNA-protein recognition techniques.

Abstract

Specific binding of proteins to DNA is one of the most common ways in which gene expression is controlled. Although general rules for the DNA-protein recognition can be derived, the ambiguous and complex nature of this mechanism precludes a simple recognition code, therefore the prediction of DNA target sequences is not straightforward. DNA-protein interactions can be studied using computational methods which can complement the current experimental methods and offer some advantages. In the present work we use physical effective potentials to evaluate the DNA-protein binding affinities for the lambda repressor-DNA complex for which structural and thermodynamic experimental data are available. The effect of conformational sampling by Molecular Dynamics simulations on the computed binding energy is assessed; results show that this effect is in general negative and the reproducibility of the experimental values decreases with the increase of simulation time considered. The free energy of binding for non-specific complexes agrees with earlier theoretical suggestions. Moreover, as a results of these analyses, we propose a protocol for the prediction of DNA-binding target sequences. The possibility of searching regulatory elements within the bacteriophage-lambda genome using this protocol is explored. Our analysis shows good prediction capabilities, even in the absence of any thermodynamic data and information on the naturally recognized sequence. This study supports the conclusion that physics-based methods can offer a completely complementary methodology to sequence-based methods for the identification of DNA-binding protein target sequences.