Tethered-hopping model for protein-DNA binding and unbinding based on Sox2-Oct1-Hoxb1 ternary complex simulations.
The sliding and hopping models encapsulate the essential protein-DNA binding process for binary complex formation and dissociation. However, the effects of a cofactor protein on the protein-DNA binding process that leads to the formation of a ternary complex remain largely unknown. Here we investigate the effect of the cofactor Sox2 on the binding and unbinding of Oct1 with the Hoxb1 control element. We simulate the association of Oct1 with Sox2-Hoxb1 using molecular dynamics simulations, and the dissociation of Oct1 from Sox2-Hoxb1 using steered molecular dynamics simulations, in analogy to a hopping event of Oct1. We compare the kinetic and thermodynamic properties of three model complexes (the wild-type and two mutants) in which the Oct1-DNA base-specific interactions or the Sox2-Oct1 protein-protein interactions are largely abolished. We find that Oct1-DNA base-specific interactions contribute significantly to the total interaction energy of the ternary complex, and that nonspecific Oct1-DNA interactions are sufficient for driving the formation of the protein-DNA interface. The Sox2-Oct1 protein-protein binding interface is largely hydrophobic, with remarkable shape complementarity. This interface promotes the formation of the ternary complex and slows the dissociation of Oct1 from its DNA-binding site. We propose a simple two-step reaction model of protein-DNA binding, called the tethered-hopping model, that explains the importance of the cofactor Sox2 and may apply to similar ternary protein-DNA complexes.
Lian
Peng
P
School of Life Science, Shandong University, Jinan, People's Republic of China.
Liu
Limin Angela
LA
Shi
Yongxiang
Y
Bu
Yuxiang
Y
Wei
Dongqing
D
D001665:Binding Sites; D001703:Biophysics / Q000379:methods*; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry*; D018398:Homeodomain Proteins / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D009154:Mutation; D027702:Organic Cation Transporter 1 / Q000737:chemistry*; D025941:Protein Interaction Mapping; D011506:Proteins / Q000737:chemistry*; D055748:SOXB1 Transcription Factors / Q000737:chemistry*; D013816:Thermodynamics
C101121:HOXB1 homeodomain protein; D018398:Homeodomain Proteins; D027702:Organic Cation Transporter 1; D011506:Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D004247:DNA