Protein-Protein Interactions Can Accelerate Transcription Factor Target Search on DNA

Protein molecules known as transcription factors (TFs) start gene expression by associating with specific promoter sites on DNA, initiating transcription. Recent studies have shown that various transcription factors interact with one another to form oligomers and phase-separated bodies. However, the impact of protein-protein interactions on the binding of TFs to their target sites on DNA remains elusive. To address this question, we developed a discrete-state stochastic model to quantitatively investigate the effect of dimerization of TFs in the target search on DNA. Using analytical calculations supported by kinetic Monte Carlo simulations, it is demonstrated that dimerization alters the effective association, dissociation, and sliding dynamics of TFs, leading to substantial changes in target search kinetics. Our results further show that the collective behavior of multiple TFs strongly depends on the dominant search regime. In particular, we identify parameter regimes in which dimerization significantly accelerates the localization of target sites, thereby enhancing the efficiency of the target search. We provide physical and chemical arguments to explain the origin of these effects and discuss recent experimental observations in light of our theoretical findings. Overall, the presented theoretical analysis indicates that tuning protein-protein interactions of TFs might be an efficient tool for the regulation of genetic information transfer.