Further information about our poster from BPS2025: GPU-accelerated residue-level model for chromatin dynamics

🔗 Links/Contacts

• Read the abstract.
• Contact me (Kieran Russell) at kor20@cam.ac.uk, follow my Bluesky account to be notified when the model paper and code are out.
• Contact my supervisor (Prof. Rosana Collepardo-Guevara) at rc597@cam.ac.uk, follow her Bluesky account for updates on the work of our lab.
• Follow Jan Huertas and Julia Maristany on Bluesky.
• Read our new preprint , a collaboration led by Huabin Zhou from the Rosen Lab at UTSW Medical Center. In this paper, we combine the new model with cryoET data to investigate how linker length modulates chromatin condensates across length scales. Steered MD is used to enforce nucleosome conformations inferred from cryoET and minimal simulation data, with the histone tails then freely sampled under different solution conditions, elucidating features of condensed chromatin on the amino acid scale.

🎞 Animations

Single fiber Debye length Hamiltonian replica exchange simulations [1] of chromatin fibers reveal how linker length governs conformational ensembles for individual chromatin fibers. For 25bp chromatin (pink), the twist of DNA limits the formation of strong face-face stacking interactions leading to a variety of less regular and more extended structures. In contrast, for 30bp chromatin (green), DNA mechanics promotes stacking interactions leading to more regular structures, dominated by face-face stacking.

Single fiber properties of chromatin carry through to the condensed phase, with simulations of tetrameric chromatin arrays revealing that 25bp chromatin forms more densely connected, less dynamic condensates with abundant inter-array face-face contacts, whilst 30bp chromatin forms less dense and more dynamic condensates due to the burial of many nucleosome faces in the regular stacked structure that dominates the conformational ensemble of the 30bp tetrameric array.

Summary video from our new collaborative preprint [7], showcasing in vitro and in situ experimental results consistent with the simulation results presented here. Read the full paper (linked above and below) for more details.

Bibliography

1. Nucleosome plasticity is a critical element of chromatin liquid–liquid phase separation and multivalent nucleosome interactions Paper from our lab describing our multiscale chromatin model, including the older, LAMMPS based residue-resolution model that provides much inspiration for this model.
2. Stability and folding pathways of tetra-nucleosome from six-dimensional free energy surface A paper from the lab of Bin Zhang, where a different residue-resolution model is used to investigate the folding of tetrameric chromatin arrays. This paper is where the symmetrized internucleosome distance features used in the structural analysis presented on the poster was proposed.
3. Multiscale modelling of chromatin organisation: Resolving nucleosomes at near-atomistic resolution inside genes Review article discussing multiscale simulations of chromatin with a detailed account of SOTA residue-resolution models.
4. OpenMM 8: Molecular Dynamics Simulation with Machine Learning Potentials The latest OpenMM publication, detailing new features of the GPU-accelerated MD package OpenMM.
5. CGeNArate: a sequence-dependent coarse-grained model of DNA for accurate atomistic MD simulations of kb-long duplexes Paper from the lab of Modesto Orozco introducing the particle based coarse-grained DNA model adapted for use in this chromatin model.
6. Coarse-grained models for simulations of multiprotein complexes: application to ubiquitin binding Kim & Hummer's 2008 paper introducing their residue-level protein model. This protein model was used in [1] and now also this work.
7. Multi-scale structure of chromatin condensates rationalizes phase separation and material properties Our new preprint, described in more detail above.
8. Short nucleosome repeats impose rotational modulations on chromatin fibre folding Paper from the lab of Sergey Grigoriyev where sedimentation coefficients from single fibers of varying NRL are presented. This experimental data is used to validate the model.
9. Nucleosome Spacing Can Fine-Tune Higher Order Chromatin Assembly Another new pre-print from the collaboration between our lab and the lab of Michael Rosen. Here extensive simulations using the minimal model are combined with experimental results to investigate the effects of nucleosome spacing and its alteration by remodellers on condensed phase behavior of chromatin.
10. Expansion of Intrinsically Disordered Proteins Increases the Range of Stability of Liquid–Liquid Phase Separation Paper from our lab exploring how single-molecule properties of IDPs contribute to different LLPS behavior.