Specificity in protein-DNA interactions: energetic recognition by the (cytosine-C5)-methyltransferase from HhaI |
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Authors: | Huang Niu MacKerell Alexander D |
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Institution: | Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, 20 N. Penn St., Baltimore, MD 21201, USA. |
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Abstract: | Sequence-specific interactions between proteins and DNA are essential for a variety of biological functions. The (cytosine-C5)-methyltransferase from HhaI (M.HhaI) specifically modifies the second base in GCGC sequences, employing a base flipping mechanism to access the target base being chemically modified. The mechanism of sequence-specific recognition of M.HhaI is not evident based on crystallographic structures, leading to the suggestion that recognition is linked to the flipping event itself, a process that may be referred to as energetic recognition. Using computational methods, it is shown that the free energy barriers to flipping are significantly higher in non-cognate versus the cognate sequence, supporting the energetic recognition mechanism. Energetic recognition is imparted by two protein "selectivity filters" that function via a "web" of protein-DNA interactions in short-lived, high energy states present along the base flipping pathway. Other sequence-specific DNA binding proteins whose function involves significant distortion of DNA's conformation may use a similar recognition mechanism. |
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Keywords: | epigenetics base flipping sequence-specific recognition molecular dynamics potential of mean force |
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