In-silico studies on structural and thermodynamics basis of interaction of lac repressor protein binding to different DNA operators

Abstract Transcription factors, which bind to a large number of sequences in the sea of genome non-specifically, affect the final outcome in a sequence-dependent manner and intrigued us to explore whether there exists any conformational preference of the DNA. Lac-repressor, binds to major groove of DNA with strong sequence specificity, also interacts with the minor groove of its operator by partially intercalating two symmetry related Leucine side-chains between two CG base pairs. We attempt to elucidate mechanisms of the structural and dynamic alterations of two different Lac operator DNA sequences upon Lac repressor recognition using molecular modelling and all-atom molecular dynamics simulations. The difference of hydrogen bonding network and deformation of DNA base pair step produce the asymmetric dynamics of the two subunits of Lac repressor protein. Variation of minor groove widths can direct overall shape complementarily between the DNA and protein surfaces indicating DNA is significantly deformed to accommodate the protein fold. Bending flexibility indirectly modulates the Lac binding activity that controls transcription efficiency. Thus we suggest that Lac operator is unique as it uses both Lock & Key mechanism for DNA recognition, where protein induced structural alteration of the receptor DNA is not required, and also Induced Fit/Conformational Selection model of recognition. Graphical Abstract Highlights Recognition of two different DNA Sequences by prokaryotic transcription factor lac repressor is modulated through asymmetric protein dynamics that have emerged in terms of conformational entropy and essential dynamics. The difference of the hydrogen bonding network and the deformation of the DNA base pair step produces the asymmetric dynamics of the two subunits of the lac repressor protein. The difference in overall protein dynamics upon interaction with DNAs of different sequences is the key feature in stabilizing the gene regulatory networks differently.