Abstract
Biological functions of DNA depend on the sequence-specific binding of DNA-binding proteins to their corresponding binding sites. Binding of these proteins to their binding sites occurs through a facilitated diffusion process that combines three-dimensional diffusion in the cytoplasm with one-dimensional diffusion (sliding) along the DNA. In this work, we use a lattice model of facilitated diffusion to study how the dynamics of binding of a protein to a specific site (e.g., binding of an RNA polymerase to a promoter or of a transcription factor to its operator site) is affected by the presence of other proteins bound to the DNA, which act as 'obstacles' in the sliding process. Different types of these obstacles with different dynamics are implemented. While all types impair facilitated diffusion, the extent of the hindrance depends on the type of obstacle. As a consequence of hindrance by obstacles, more excursions into the cytoplasm are required for optimal target binding compared to the case without obstacles.
Highlights
Biological functions of DNA depend on the sequence-specific binding of DNA-binding proteins to their corresponding binding sites
This theoretical model has been strongly supported by experimental techniques that directly showed the number of basepairs scanned via 1D sliding,[8,9,10] and the average fraction of time the DNA-binding proteins (DBPs) remains bound to the DNA before unbinding.[11,12]
One key feature that is different in cells compared to in vitro is that the cytoplasm is not a dilute solution, but a rather crowded environment that can be occupied up to 40% by macromolecules.[28,29]
Summary
Since it was proposed, facilitated diffusion has been the subject of much theoretical,[13,14,15,16,17,18] experimental[4,19,20,21,22,23,24] and computational[25,26,27] efforts. Interest in facilitated diffusion has been renewed by the direct observation of facilitated diffusion in bacterial cells using single-molecule techniques.[11,12] One key feature that is different in cells compared to in vitro is that the cytoplasm is not a dilute solution, but a rather crowded environment that can be occupied up to 40% by macromolecules.[28,29] The presence of these macromolecules (crowders) inside the cells has effects on diffusion,[30,31,32] enzymatic reactions,[33,34,35,36] protein folding[37,38,39,40] and gene expression.[41,42,43] In addition, the DNA itself is covered with proteins that bind to the DNA in order to perform functions such as transcription, DNA repair and gene regulation.[1,44,45,46] the DNA itself is spatially organized and compacted by histones in eukaryotes and nucleoid-associated proteins in bacteria.[47,48] the DNA is highly occupied (B30%) by DBPs that affect the facilitated diffusion process.
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