Figure 2.

Illustration of the energy levels and the kinetic model for the two TF species system with a nonspecific genomic background. (A) Binding of TFs to the DNA reduces the energy by E_ns < 0 compared to the unbound reference state with energy E_free = 0. Additional energy can be gained through sequence-specific contacts (not shown). Upon dimerization of TFs in solution or on the DNA, the energy is further reduced by the interaction energy E_int ≤ 0. The TFs bind to their target site with a specific binding energy E_T. At small dimerization energies E_int, full promoter activation will be reached via the monomer pathway, where TFs arrive at their target independently and consecutively. At large E_int, on the other hand, TFs will predimerize in the DNA-background or in solution and arrive to the targets simultaneously through the dimer pathway. (B) Transcription factors dimerize in solution and bind to the DNA in diffusion-limited binding reactions with a rate constant k_a. The dissociation rate of a free dimer k_d and the dissociation rate k_off of a TF from a DNA site depend on the corresponding energies and follow from detailed balance as explained in the main text. Dimers and monomers can randomly diffuse along the DNA with a rate k_sl, which becomes site-dependent when the binding energy is sequence-specific. When the dissociation of a monomer requires the simultaneous dissociation from a cooperatively bound partner, its off-rate k_off decreases by a factor 1/ω.