Molecular Mechanism behind Cholinium-Taurate Ionic Liquid in Stabilisation of HDAC2 for Alcohol Use Disorders: Insights from DFT and MD Simulations

Abstract

The current 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), a crucial enzyme linked to alcohol use disorder (AUD). The hallmarks of AUD, a worldwide health burden, include epigenetic dysregulation, in which HDAC2 plays a major 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 stabilization is mediated by intricate hydration networks, water-bridged H-bonds, and diverse non-covalent interactions (NCI), as confirmed through rigorous structural analyses. Our findings highlight [Cho]+[Tau]- IL a robust stabilizer and potential inhibitor 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.