Disordered Tails Shape DNA Specificity of Myc:Max via Transient Competition

Intrinsically disordered regions (IDRs) are ubiquitous in eukaryotic transcription factors, yet the high prevalence of negatively charged IDRs presents a biophysical paradox due to their expected electrostatic repulsion from the DNA backbone. In the Myc:Max bHLH-LZ transcription factor complex, both monomers possess diverse terminal tails that confer an overall net negative charge, stronger in one monomer than the other, a feature proposed to influence DNA binding. Here, we investigate the molecular mechanism by which these negative tails modulate recognition kinetics, thermodynamics and specificity using coarse-grained molecular dynamics simulations. We demonstrate that negatively charged tail of the Max monomer significantly accelerates the target search process by shifting the dominant linear diffusion mode from sliding to hopping that is characterized with higher diffusion coefficient. This acceleration is driven by a dynamic autoinhibitory mechanism in which the negative tails transiently competes with DNA for interactions with the positively charged DNA-binding domain. Crucially, this dynamic screening increases specificity and functions as a kinetic filter, preferentially reducing dwell times on decoy sequences while preserving high affinity binding to cognate sites. The increase in specificity is achieved by intramolecular interactions instead of base-specific interactions with the DNA. We further show that while phosphorylation amplifies this acceleration, it imposes a trade-off by destabilizing target binding, suggesting the charge density of the tails is evolutionarily optimized. Finally, we reveal that attractive electrostatic interactions between the Myc and Max tails in the heterodimer partially attenuate this acceleration, adding a layer of regulation. Our findings suggest that negatively charged tails function as dynamic kinetic gatekeepers, optimizing the trade-off between rapid genomic search and high-fidelity discrimination.