(435a) Fingerprinting Histone Tail Modifications at Atomistic Resolution in the Human Nucleosome

Eukaryotic cells package their genetic material into chromatin in a hierarchical manner by wrapping DNA around an octamer of histone proteins called a nucleosome. The N-terminal tails of the histone proteins undergo numerous post-translational modifications (PTMs) that are hallmarks of various disease states like cancer and play a key role in regulating transcription. The mechanisms of how atomistic changes to the structure result in these functional outcomes are not well understood. Using a combination of all-atomistic equilibrium and umbrella sampling molecular dynamics (totaling in >30 ms of total simulation time), we characterized the dynamics of the most clinically relevant (H3) N-terminal tail.
In this presentation, we report fingerprinting seven different PTMs of the H3 histone, such as methylation (mono, di, tri), acetylation, and phosphorylation of key H3 residues. Each system contains greater than 300,000 atoms which include the whole nucleosome, explicit water, and ions. We analyzed histone tail residues for contacts with DNA, hydrogen bonding with water, cations, and anions. Further, we report the radius of gyration, end-to-end distances, and secondary structure analysis for all PTMs. The study revealed a novel behavior of three segmented regions of the H3 tails, with each segment separated by a proline residue. Although there are subtle differences in dynamics with different PTMs, the segmental regions we present in this work hold regardless of modifications. This work provides foundational knowledge to diseases triggered via diet, chemical exposure, viral infections, and the environment.