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To resolve how sequence divergence alters genome packaging over macroevolutionary timescales, the authors constructed and simulated nucleosome structures across 3,241 organisms spanning 1.5 billion years of evolution. Mapping this evolutionary landscape is essential for understanding how local protein mutations dictate higher-order chromatin phase behavior and nuclear architecture. Electrostatic profiling and coarse-grained molecular dynamics simulations reveal that histone diversification directly modulates the electrostatic landscape of nucleosomes, driving radical divergence in bulk chromatin compaction and phase separation.
Over 1.5 billion years of evolution, subtle electrostatic drift in histone sequences systematically reprogrammed the mesoscale phase behavior and physical compaction of eukaryotic genomes.
Nucleosomes are structures made up of proteins called histones that bind and compact DNA, driving the mesoscale organization of the chromatin polymer. Although histone proteins have diversified over evolutionary time, their contributions to the corresponding diversification of chromatin structure are poorly understood. Here, we mine protein databases for histones and create \emph{in silico} nucleosomes for 3241 organisms spanning $>$1.5B years of evolution. Using a combination of electrostatic calculations and coarse-grained molecular dynamics simulations, we reveal extensive biophysical diversification of the nucleosome unit. Finally, we perform coarse-grained oligonucleosomal simulations on a subset of evolutionarily and biophysically divergent nucleosomes, demonstrating dramatic differences in bulk phase behavior of chromatin. Taken together, our results suggest a paradigm in which histones may have evolved to facilitate particular types of mesoscale chromatin behavior.