Theory on the mechanism of rapid binding of transcription factor proteins at specific-sites on DNA

TL;DR

This paper presents a revised theoretical model explaining how transcription factors rapidly locate specific DNA sites by combining 3D diffusion with 1D sliding, resulting in enhanced binding rates.

Contribution

It introduces a new theoretical framework that quantifies the rate enhancement of DNA-protein binding through 1D diffusion and state switching mechanisms, aligning with experimental data.

Findings

Rate enhancement proportional to maximum sliding length LA

Efficient site location via cyclic switching of binding states

Asymptotic rate limit increases with DNA length

Abstract

We develop revised theoretical ideas on the mechanism by which the transcription factor proteins locate their specific binding sites on DNA faster than the three-dimensional (3D) diffusion controlled rate limit. We demonstrate that the 3D-diffusion controlled rate limit can be enhanced when the protein molecule reads several possible binding stretches of the template DNA via one-dimensional (1D) diffusion upon each 3D-diffusion mediated collision or nonspecific binding event. The overall enhancement of site-specific association rate is directly proportional to the maximum possible sliding length (LA, square root of (6Do/kr) where Do is the 1D-diffusion coefficient and kr is the dissociation rate constant associated with the nonspecific DNA-protein complex) associated with the 1D-diffusion of protein molecule along DNA. Upon considering several possible mechanisms we find that the DNA binding proteins can efficiently locate their cognate sites on DNA by switching across fast-moving, slow-moving and reading states of their DNA binding domains in a cyclic manner. Irrespective of the type of mechanism the overall rate enhancement factor asymptotically approaches a limiting value which is directly proportional to LA as the total length of DNA that contains the cognate site increases. These results are consistent with the in vitro experimental observations.