Recent years have witnessed an explosion of interest in computational studies of DNA binding proteins, including both coarsegrained and atomistic simulations of transcription factor-DNA recognition, to understand how these transcription factors recognize their binding sites on the DNA with such exquisite specificity. The present study performs microsecond time scale all-atom simulations of the dimeric form of the lactose repressor (LacI), both in the absence of any DNA and in the presence of

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... h specific and nonspecific complexes, considering three different DNA sequences. We examine, specifically, the conformational differences between specific and nonspecific protein−DNA interactions, as well as the behavior of the helix-turn-helix motif of LacI when interacting with the DNA. Our simulations suggest that stable LacI binding occurs primarily to bent A-form DNA, with a loss of LacI conformational entropy and optimization of correlated conformational equilibria across the protein. In addition, binding to the specific operator sequence involves a slightly larger number of stabilizing DNA−protein hydrogen bonds (in comparison to nonspecific complexes), which may account for the experimentally observed specificity for this operator. In doing so, our simulations provide a detailed atomistic description of potential structural drivers for LacI selectivity.