Pushing the experimental resolution boundary in chromatin fibre organisation using multiscale simulations.

The multiscale organisation of chromatin arises from the interplay of intermolecular interactions, physical constraints, and the physicochemical properties of the nuclear environment. These processes span a wide range of spatial and temporal scales. At the scale of a few angstroms, atomic interactions between histone residues, DNA, metabolites, and solvent molecules occur on picosecond to nanosecond timescales. At the nanometre scale, nucleosomes and their arrays undergo conformational changes, sliding, and breathing motions on microsecond to millisecond timescales. At the micrometre scale, chromatin domains and whole chromosomes reorganise within the nucleus over seconds to hours. No single experimental technique can capture this continuum in its entirety. Structural and imaging methods each probe distinct regimes of this hierarchy, leaving gaps in our understanding of how local interactions give rise to higher-order organisation. In this Opinion, we discuss how integrating experiments with multiscale simulations provides a quantitative framework to bridge scales and uncover the mechanisms linking chemically specific molecular interactions to chromatin folding, dynamics, and phase behaviour.