Physical limits on cooperative protein-DNA binding and the kinetics of combinatorial transcription regulation

TL;DR

This paper develops a theoretical model to understand the physical limits and kinetics of cooperative protein-DNA binding, revealing optimal interaction regimes for efficient gene regulation.

Contribution

It introduces a simplified model for two interacting transcription factors, analyzing their search and binding kinetics, and identifies regimes that optimize gene regulation efficiency.

Findings

Weak and strong TF-TF interactions are favorable for regulation.

Intermediate interactions lead to slow genetic responses.

Optimal interaction regimes balance speed and binding strength.

Abstract

Much of the complexity observed in gene regulation originates from cooperative protein-DNA binding. While studies of the target search of proteins for their specific binding sites on the DNA have revealed design principles for the quantitative characteristics of protein-DNA interactions, no such principles are known for the cooperative interactions between DNA-binding proteins. We consider a simple theoretical model for two interacting transcription factor (TF) species, searching for and binding to two adjacent target sites hidden in the genomic background. We study the kinetic competition of a dimer search pathway and a monomer search pathway, as well as the steady-state regulation function mediated by the two TFs over a broad range of TF-TF interaction strengths. Using a transcriptional AND-logic as exemplary functional context, we identify the functionally desirable regime for the interaction. We find that both weak and very strong TF-TF interactions are favorable, albeit with different characteristics. However, there is also an unfavorable regime of intermediate interactions where the genetic response is prohibitively slow.