Conformational Changes in the Lac Repressor Protein Effect DNA Loop Energetics and Topology

Abstract

DNA looping mediated by the Lac repressor protein is a classic exemplar for understanding protein-DNA interactions and allosteric mechanisms in gene regulation. When the repressor protein binds to two distant operator sites on substrate DNA, it causes the formation of DNA loops. Most of the previous study of this system has focused on either the properties of the DNA loop created by the protein-DNA interaction or seeks to explain the possible conformational changes of the protein itself. Here we take a combined approach by considering the effects of protein deformation on the topology and energetics of the induced looped-DNA. We begin by creating a collection of 3D atomic coordinate models of the protein to simulate the structural fluctuation consistent with earlier studies. By incrementally rotating segments of the protein about likely sites of flexibility these new models provide a large distribution of constraint parameters for the generation of looped-DNA coordinates. We then employ a novel approach to obtain minimum energy looped structure whereby the potential energy of elastic deformation is optimized. In this way we are able to describe energy landscapes that provide clues to how variations in protein structure contribute to DNA loop stability and topology.