Impact of Histone Acetylation on Chromatin Folding: Insight from Molecular Modeling at Multiple Scales

In eukaryotic cell nuclei, the genome presents a complex hierarchical three-dimensional structure, established by the winding of long DNA molecules around specific proteins known as histones. These complexes, called nucleosomes, are the fundamental structural blocks of chromatin fibers. Changes in histone dynamics exert a critical impact on DNA structural features, thereby influencing chromatin folding and genome accessibility. In particular, the transcription of specific genes is regulated by structural changes that grant or deny access to genetic information, known as epigenetic modifications (EMs). Among these, post-transcriptional modifications (PTMs) refer to chemical alterations of residues in histone tails. Notably, changes in normal PTMs patterns might potentially trigger abnormal genome activities, commonly associated with several human diseases. Moreover, experimental studies have pointed out that specific PTMs can impact chromatin folding resulting in different mechanics of the cell nucleus. However, to achieve a complete understanding of how EMs affect chromatin spatial organization, and ultimately the nucleus mechanics, the sole experimental studies are not sufficient. In fact, although the link between PTMs and gene transcription is undeniable, the structural and dynamic mechanisms through which these modifications influence the transcription are still unknown. Therefore, it is crucial to combine them with computational approaches allowing us to investigate such processes at the molecular level. In particular, Molecular Modeling and Molecular Dynamics (MD) simulations have emerged as powerful tools for studying molecular processes at the nanoscale. In this context, this work is focused on the analysis of two histone H3 lysine acetylations that are known to affect gene expression and improve the mechanics of the nucleus. By leveraging all-atoms MD, Replica Exchange Molecular Dynamics (REMD), and Coarse-Grained (CG) MD simulations, we investigated at different scales the effect of these PTMs on the dynamics of chromatin, from the H3 N-terminal tail to the protein-protein and protein-DNA interactions in a dinucleosome system. Both MD and REMD analysis showed a less structured H3 N-terminus in both acetylated models, where lysins were also less exposed to the environment. At a larger scale, for both acetylated models, the inter-nucleosome distance was reduced as well as the protein-DNA interface area. These insights suggest how such acetylation might alter chromatin folding and DNA accessibility, paving the way for further studies investigating the correlation with epigenetics marks associated with abnormal gene activities.