TAL (transcriptional activator-like) effectors are DNA-binding repeat proteins recently shown to recognize their target sites by an unprecedented, 1:1 mapping between repeat residues and DNA bases. The structural basis for this recognition is not known; in particular, it is not clear whether such 1:1 recognition can be accommodated by standard major-groove readout of B-form DNA. Here we describe a structure prediction protocol tailored to the TAL-DNA system, and report simulation results that shed light on observed repeat-base associations and overall TAL structure. Our models demonstrate that TAL-DNA interactions can be explained by a model in which the TAL repeat domain forms a superhelical repeat structure that wraps around undistorted B-form DNA, paralleling the geometry of the major groove, with contacts between position 13 of each repeat and its associated base pair on the sense strand determining the specificity of DNA recognition.
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