Energetic funnel facilitates facilitated diffusion

TL;DR

This paper uncovers an energetic funnel in DNA around transcription factor binding sites that, by guiding sliding proteins, accelerates the target search process, explaining how association rates surpass diffusion limits.

Contribution

It reveals the presence of an energy landscape funnel around binding sites and demonstrates its role in speeding up transcription factor-DNA association.

Findings

Funnel linked to AT base composition gradients.

Funnel enhances target search probability.

Funnel accelerates association speed.

Abstract

Transcription factors are able to associate to their binding sites on DNA faster than the physical limit posed by diffusion. Such high association rates can be achieved by alternating between three-dimensional diffusion and one-dimensional sliding along the DNA chain, a mechanism dubbed Facilitated Diffusion. By studying a collection of transcription factor binding sites of Escherichia coli from the RegulonDB database and of Bacillus subtilis from DBTBS, we reveal a funnel in the binding energy landscape around the target sequences. We show that such a funnel is linked to the presence of gradients of AT in the base composition in the DNA region around the binding sites. An extensive computational study of the stochastic sliding process along the energetic landscapes obtained from the database shows that the funnel can significantly enhance the probability of transcription factors to find their target sequences when sliding in their proximity. We demonstrate that this enhancement leads to a speed-up of the association process.