Proteins that bind to specific sequences in long DNA molecules have to locate their target sites amid myriad alternative sequences, yet they do so at remarkably rapid rates, sometimes approaching 1010 M−1·s−1. Hence, it has been asserted widely that binding to specific DNA sites can surpass the maximal rate for 3D (three-dimensional) diffusion through solution and that this could only be accounted for by a reduction in the dimensionality of the search for the target in effect by 1D (one-dimensional) diffusion (or ‘sliding’) along the DNA contour. It will be shown here that there is, in fact, no known example of a protein binding to a specific DNA site at a rate above the diffusion limit, and that the rapidity of these reactions is due primarily to electrostatic interactions between oppositely charged molecules. It will also be shown that, contrary to popular belief, reduced dimensionality does not, in general, increase the rate of target-site location but instead reduces it. Finally, it will be demonstrated that proteins locate their target sites primarily by multiple dissociation/reassociation events to other (nearby or distant) sites within the same DNA molecule, and that 1D diffusion is limited to local searches covering ∼50 bp around each landing site.

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