Polymer compaction and bridging-induced clustering of protein-inspired patchy particles

Abstract

There are many proteins or protein complexes which have multiple DNA binding domains. This allows them to bind to multiple points on a DNA molecule (or chromatin fibre) at the same time. There are also many proteins which have been found to be able to compact DNA in vitro, and many others have been observed in foci or puncta when fluorescently labelled and imaged in vivo. In this work we study, using coarse-grained Langevin dynamics simulations, the compaction of polymers by simple model proteins and a phenomenon known as the "bridging-induced attraction". The latter is a mechanism observed in previous simulations [Brackley et al., Proc. Natl. Acad. Sci. USA 110 (2013)], where proteins modelled as spheres form clusters via their multivalent interactions with a polymer, even in the absence of any explicit protein-protein attractive interactions. Here we extend this concept to consider more detailed model proteins, represented as simple "patchy particles" interacting with a semi-flexible bead-and-spring polymer. We find that both the compacting ability and the effect of the bridging-induced attraction depend on the valence of the model proteins. These effects also depend on the shape of the protein, which determines its ability to form bridges.

Transcription modulates chromatin dynamics and locus configuration sampling

“…3b) showed a pronounced reduction at protein binding sites (ATAC-seq peaks, red bars). This is consistent with these sites being involved in bridging interactions with distant (> 100 kbp) regions, leading to the creation of active protein clusters through the bridging-induced attraction 15,22 . Some, but not all, H3K27ac marked regions (open chromatin, yellow shading) also displayed a reduced localness of interactions.…”

“…In the present analysis we predominantly consider active chromatin regions, but this model could also be extended to account for repressed regions of the genome. An important feature is that proteins tend to come together into clusters; this is driven by a mechanism known as the "bridging induced attraction" 15,22 and is a consequence of a protein's ability to form molecular bridges. The clusters form around two or more protein binding sites on the chromatin and represent the foci or "phase-separated droplets" of transcription associated proteins observed in recent microscopy studies 23,24 .…”

Complex small-world regulatory networks emerge from the 3D organisation of the human genome

“…Strikingly, bound TFs spontaneously cluster, despite there being no attractive interactions between TUs or between TFs. Such clustering is driven by the “bridging-induced attraction” 16 , 24 , 25 that arises due to a positive feedback: when a TF forms a molecular bridge between two chromatin regions and forms a loop, the local chromatin concentration increases, making further TF binding more likely. Clusters then grow until limited by entropic costs of crowding (Fig.…”

Complex small-world regulatory networks emerge from the 3D organisation of the human genome

“…Strikingly, bound TFs spontaneously cluster, despite there being no attractive interactions between TUs or between TFs. Such clustering is driven by the "bridging-induced attraction" [16,24,25] that arises due to a positive feedback: when a TF forms a molecular bridge between two chromatin regions and forms a loop, the local chromatin concentration increases, making further TF binding more likely. Clusters then grow until limited by entropic costs of crowding (Fig.…”