Chiral Recognition of β-Cyclodextrin for Propranolol Driven by Coordinated Multiple Effects: A Multi-Scale Molecular Dynamics Study

Abstract A comprehensive understanding of cyclodextrin-chiral drug interactions is crucial for efficient enantiomer separation. The chiral recognition mechanism of β-cyclodextrin (β-CD) toward propranolol was investigated using a multi-scale framework integrating molecular dynamics (MD), umbrella sampling (US) and density functional theory (DFT) calculations. The MD analysis showed that among the four binding modes, the R-type enantiomer adopting the isopropyl insertion mode (RIpr@CD) has the best structural stability. Subsequently, US simulations and the MM-PBSA showed that RIpr@CD achieved the optimal thermodynamic stability, with the most negative PMF (−34.84 kJ/mol) and MM-PBSA (−18.58 kJ/mol) values. Furthermore, the independent gradient model based on Hirshfeld partition (IGMH) analysis and electrostatic potential (ESP) mapping confirm that the optimal binding of RIpr@CD stems from the formation of more continuous van der Waals (vdW) interactions and stronger hydrogen bonds (H-bonds). These findings provide a fundamental understanding of the chiral recognition mechanisms mediated by various forces and establish a robust methodological framework for the rational design of efficient chiral separation systems.