Fly-casting in protein-DNA binding: Frustration between protein folding and electrostatics facilitates target recognition

Molecular plasticity, the key to many biomolecular self-assembly processes, and electrostatic steering, which guides proteins to DNA, are shown to be coupled and to facilitate DNA search. While protein flexibility is involved in induced-fit recognition and to a larger extent in intrinsically unstructured DNA binding proteins, we show that through a "tidal force" the electrostatic field of the DNA can induce flexibility and the partial unfolding of a two-state folding protein, thereby reducing its folding barrier and, thus, stimulating fly-casting. The protein binds DNA nonspecifically in a partially folded state and completes its folding when it binds the specific site. The interplay between fly-casting and electrostatics is observed even for weak electrostatic forces and is expected to vary with the electrostatic screening due to salt and the intrinsic folding barrier, both of which can be modulated experimentally.