Protein search processes mediated by chromatin topology

We investigate the role of compaction of chromatin domains in modulating search kinetics of proteins. Collapsed conformations of chromatin, characterised by long loops which bring distant regions of the genome into contact, and manifested structurally as Topologically Associated Domains (TADs) affect search kinetics of DNA associating transcription factors and other proteins. In this study, we investigate the role of the compactness of chromatin on the dynamics of proteins using a minimal model. Using analytical theory and simulations, we show that an optimal compaction exists for which the search time of proteins on a chromatin-like polymer backbone is minimum. We show that while bulk diffusion is an advantageous search strategy for extended polymers, for highly folded polymer domains, intersegmental transfers allow optimal search. We extend these results to more detailed polymer models - using the Freely Rotating Chain model, a LJ bead-spring polymer model, which approximates chromatin behavior. We show that our results continue to hold for these polymer models, with a minimum residence time at an optimum polymer compaction. Finally, we also analyse the dynamics of proteins on networks generated using experimental chromatin conformation data from 8355 TADs extracted from human chromosomes. Our analysis suggests that TADs exist near this zone of optimality, indicating that chromatin conformations can play a crucial role in modulating protein search strategies.