Molecular Dynamics Insights into the Recognition of Histone Crotonylation by the AF9 YEATS Domain

Epigenetics studies regulatory mechanisms that control gene expression without altering DNA sequence. Among these mechanisms, post-translational modifications (PTMs) integrate cellular metabolic and inflammatory signals into transcriptional programs. Within this context, YEATS domains are epigenetic readers that recognize lysine acylations on histones, showing preference for bulky acyl marks, such as crotonylation.

To investigate the molecular basis of epigenetic mark recognition, molecular dynamics (MD) simulations were performed on the complex formed by histone H3 crotonylated on lysine 9 (H3K9cr) and the YEATS domain of the human protein AF9. Analysis of trajectories revealed a stable binding mode with moderate conformational fluctuations. Structural characterization highlighted the critical role of the aromatic residues F28, F59 and Y78 in forming the binding pocket, where they establish a “sandwich-like” π stacking interaction with the crotonylated lysine, in agreement with literature.(1) Conformational dynamics were carried out and the energetic contributions of non-covalent interactions involving these aromatics residues were calculated. This allowed us to get a comprehensive description of the molecular processes underlying ligand recognition.

Overall, this study elucidates the structural and energetic basis of cronoyl-lysine recognition by the AF9 YEATS domain, providing insights into the specificity of epigenetic reader domains and supporting the future development of therapeutic strategies targeting YEATS domains.

1. Li X, Liu S, Li X, Li XD. YEATS Domains as Novel Epigenetic Readers: Structures, Functions, and Inhibitor Development. ACS Chem Biol. 2023;18(4):994–1013. doi:10.1021/acschembio.1c00945