How one-dimensional diffusion of transcription factors are affected by obstacles: coarse-grained molecular dynamics study

Abstract

Transcription activation requires transcription factors (TFs) to search their cognate sites in genomic DNA. Efficient search of TFs is thought to be realised via facilitated diffusion that combines three-dimensional and one-dimensional diffusions. In vivo, one-dimensional diffusion along DNA can be hampered by many other DNA binding proteins that may work as obstacles. Whether and how TFs can bypass the obstacles are largely unknown. Here, we address the movement of TFs along double stranded DNA with bound obstacles by performing coarse-grained molecular dynamics simulations with software CafeMol. The simulations showed that a TF, the winged-helix motif of genesis, can bypass two obstacle molecules, tetracycline repressor and EcoRI, in markedly different probabilities. Bypassing EcoRI was much more difficult probably because it wraps DNA. We found that the obstacle molecules enhanced microscopic dissociation of the TF from DNA via weakened electrostatic attractions. Moreover, bypassing movements were strongly dependent on ion concentration in solution.

Keywords:

• MD simulations
• protein–nucleic acid interactions
• protein–protein interactions