How does a protein find its site on DNA?
Leonid Mirny

Recognition and binding of specific sites on DNA by proteins is central for many cellular functions such as transcription, replication, and recombination. In the process of recognition, a protein rapidly searches for its specific site on a long DNA molecule and then strongly binds this site. Here we aim to find a mechanism that can provide both a fast search (1-10 sec) and high stability of the specific protein-DNA complex (K_d = 10^{-15}-10^{-8} M).

Earlier studies have suggested that rapid search involves the sliding of a protein along the DNA. We consider sliding as a one-dimensional (1D) diffusion in rough energy landscape formed by the energy of binding to consecutive sites on the DNA. Our analytical results and computer simulations demonstrate that, in spite of the landscape's roughness, rapid search can be achieved if 1D sliding is accompanied by 3D diffusion. We estimate the range of the specific and non-specific DNA-binding energy required for rapid search and suggest experiments that can test 1D/3D mechanism. We show that optimal search requires a protein to spend half of time sliding along the DNA and half diffusing in 3D.

We also establish that, paradoxically, realistic energy functions cannot provide both rapid search and strong binding of a rigid protein. To reconcile these two fundamental requirements we propose a search-and-fold mechanism that involves the coupling of protein binding and protein folding.

Our mechanism demonstrates functional importance of partial unfolding and induced folding observed in DNA-binding proteins. Proposed mechanism also provides a new framework for interpretation of experimental and structural data on protein-DNA interactions.