Facilitated diffusion framework for transcription factor search with conformational changes

TL;DR

This paper presents a detailed facilitated diffusion model for transcription factor search mechanisms involving conformational changes, deriving exact search times and comparing with experimental data, highlighting the importance of DNA conformation.

Contribution

It introduces a three-mode search framework with conformational switching, providing exact expressions for search times and analyzing the impact of DNA structure and conformational dynamics.

Findings

Fast search times require coiled DNA conformation.

Frequent conformational changes enable rapid searches even with immobilized recognition states.

Model aligns with experimental data on Lac repressor search dynamics.

Abstract

Cellular responses often require the fast activation or repression of specific genes, which depends on Transcription Factors (TFs) that have to quickly find the promoters of these genes within a large genome. Transcription Factors (TFs) search for their DNA promoter target by alternating between bulk diffusion and sliding along the DNA, a mechanism known as facilitated diffusion. We study a facilitated diffusion framework with switching between three search modes: a bulk mode and two sliding modes triggered by conformational changes between two protein conformations. In one conformation (search mode) the TF interacts unspecifically with the DNA backbone resulting in fast sliding. In the other conformation (recognition mode) it interacts specifically and strongly with DNA base pairs leading to slow displacement. From the bulk, a TF associates with the DNA at a random position that is correlated with the previous dissociation point, which implicitly is a function of the DNA structure. The target affinity depends on the conformation. We derive exact expressions for the mean first passage time (MFPT) to bind to the promoter and the conditional probability to bind before detaching when arriving at the promoter site. We systematically explore the parameter space and compare various search scenarios. We compare our results with experimental data for the dimeric Lac repressor search in E.Coli bacteria. We find that a coiled DNA conformation is absolutely necessary for a fast MFPT. With frequent spontaneous conformational changes, a fast search time is achieved even when a TF becomes immobilized in the recognition state due to the specific bindings. We find a MFPT compatible with experimental data in presence of a specific TF-DNA interaction energy that has a Gaussian distribution with a large variance.