title: Physical limits on cooperative protein-DNA binding and the kinetics of combinatorial transcription regulation.
abstract: Much of the complexity observed in gene regulation originates from cooperative protein-DNA binding. Although 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.
authors.affiliation: Departament de Fisica Fonamental, Facultat de Fisica, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Nico
authors.initials: N
authors.lastname: Geisel
authors.forename: Ulrich
authors.initials: U
authors.lastname: Gerland
mesh_terms: D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D007700:Kinetics; D008954:Models, Biological; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D013816:Thermodynamics; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D014157:Transcription Factors; D004247:DNA