Nine of the top-ten drugs, which account for more than US $50 billion in global sales in 2004, have chiral active ingredients [1]. Molecular docking in canonical ensemble, molecular dynamics (MD), and grand canonical Monte Carlo (GCMC) simulations were used to obtain insight into the loading, the preferential adsorption sites and configurations, and the stability of (R,R)-hydrobenzoin modifier adsorbed in microporous zeolite HY. This assembly was previously shown [2] to be capable of separating chiral compounds; however, the separation mechanism is unknown. Combined results obtained from these molecular simulations successfully established the basis for the fundamental understanding of separation mechanism for this chiral separation/adsorption system. This understanding will help in engineering new chiral environment to enhance separation of more effective and safer drugs from the currently unresolved chiral pharmaceuticals. Based on physisorption of the hydrobenzoin modifier in zeolite HY, molecular docking utilizing the Compass force field and Monte Carlo minimization algorithm predicted two preferential adsorption sites for hydrobenzoin: one at 12-membered ring window, and the other at 4-membered ring of zeolite HY. However, equilibrium MD simulation indicated that only hydrobenzoin located at the 12-membered ring window was stable (i.e., remained) at the original adsorption site during the time length of 1 ns at 294 K in the presence of valinol. Valinol is one of the chiral compounds that has been resolved using the chiral separation system consisting of zeolite HY modified by adsorbed hydrobenzoin [2]. Furthermore, configurational bias GCMC simulation for the relatively large hydrobenzoin sorbate (molecular size of ~8.5 Å) compared to the zeolite HY supercage (diameter of ~12.0 Å) suggested that the average loading level was one hydrobenzoin molecule per supercage. Supercages are the repeating sphere-like cavities connected to each other in three dimensions in the zeolite HY structure. Based on the equilibrium MD and the configurational bias GCMC simulations of chiral compound valinol sorbed in zeolite HY modified by previously adsorbed hydrobenzoin, the separation mechanism was determined to be related to the formation of complex between a single hydrobenzoin molecule and a single valinol molecule in the zeolite HY supercage.

[1] Thayer A. Trial separations. Chemical & Engineering News. 2005;83(36):49-53.

[2] Manning MP, Warzywoda J, Karahan O, Sacco A Jr. Enantioselective adsorption of hydrobenzoin on zeolite Beta. In: van Steen E, Callanan LH, Claeys M, eds. Studies in Surface Science and Catalysis. Amsterdam: Published Elsevier; 2004;154A:1957-1960.