Molecular mechanism behind the cholinium-taurate ionic liquid in stabilisation of HDAC2 for alcohol use disorders: insights from DFT and MD simulations.

This study explores how an active pharmaceutical ingredient-ionic liquid (API-IL), cholinium taurate ([Cho]+[Tau]-) IL, may alter the structural and functional stability of histone deacetylase 2 (HDAC2), which is a crucial enzyme linked to alcohol use disorder (AUD). A particular hallmark of AUD, which is a worldwide health burden, is epigenetic dysregulation, in which HDAC2 plays a significant role in gene silencing and chronic neuroplastic alterations. Leveraging the unique physicochemical properties of [Cho]+[Tau]-IL, including hydrogen bond (H-bond) formation and structural reinforcement, we explored its therapeutic potential through comprehensive computational approaches. Density functional theory (DFT) analyses provided insights into the hydration and stability profiles of [Cho]+[Tau]-IL, while 200 ns molecular dynamics (MD) simulations elucidated its interaction with HDAC2 at the molecular level. Strikingly, the [Tau]- ion emerged as a key modulator of HDAC2 stability, facilitating conformational transitions in the enzyme's secondary structure, notably from turns to helices. This stabilisation was mediated by intricate hydration networks, water-mediated H-bonds, and diverse non-covalent interactions (NCIs). The rigorous nature of our structural analyses confirmed the potential of [Cho]+[Tau]-IL as a robust stabiliser of HDAC2, offering a novel therapeutic avenue for AUD treatment. This work underscores the promise of API-ILs in targeting epigenetic regulators and advancing strategies for AUD, providing a solid foundation for future research in this area.