Theory on the mechanisms of combinatorial binding of transcription factors with DNA

TL;DR

This paper presents a theoretical framework for understanding how transcription factors bind to DNA in a combinatorial manner through three mechanisms, analyzing their efficiency and cooperative effects via simulations.

Contribution

It introduces a detailed theoretical model of monomer, hetero-oligomer, and recruitment pathways for TF-DNA binding, including simulation-based insights.

Findings

Binding efficiency decreases with more TFs in a power law.

Power law exponent depends on TF number, initial distance, and hop size.

Cooperative binding emerges from protein-protein interactions.

Abstract

We develop a theoretical framework on the mechanism of combinatorial binding of transcription factors (TFs) with their specific binding sites on DNA. We consider three possible mechanisms viz. monomer, hetero-oligomer and coordinated recruitment pathways. In the monomer pathway, combinatorial TFs search for their targets in an independent manner and the protein-protein interactions among them will be insignificant. The protein-protein interactions are very strong so that the hetero-oligomer complex of TFs as a whole searches for the cognate sites in case of hetero-oligomer pathway. The TF which arrived first will recruit the adjacent TFs in a sequential manner in the recruitment pathway. The free energy released from the protein-protein interactions among TFs will be in turn utilized to stabilize the TFs-DNA complex. Such coordinated binding of TFs in fact emerges as the cooperative effect. Monomer and hetero-oligomer pathways are efficient only when few TFs are involved in the combinatorial regulation. Detailed random walk simulations suggest that when the number of TFs in a combination increases then the searching efficiency of TFs in these pathways decreases with the increasing number of TFs in a power law manner. The power law exponent associated with the monomer pathway seems to be strongly dependent on the number of TFs, distance between the initial position of TFs from their specific binding sites and the hop size associated with the dynamics of TFs on DNA.