The Development And Application Of A Molecular Dynamics/Quantum Mechanics Approach For Rank-ordering CD-ligand Binding Affinity

Cyclodextrins (CDs) are bucket shaped cyclic oligosaccharides consisting of D-glucopyranose units by α-1,4 glycosidic bond. The most common α-, β-, γ-CD are composed of 6,7,8 glucose units, respectively. Their properties of hydrophilic external surface and hydrophobic internal cavity make them possess remarkable capability of encapsulating a variety of non-polar or weakly polar guest molecules in aqueous solutions. They have been widely used in industrial, agricultural, pharmaceutical, food, chiral resolution and environmental applications since they are non-toxic, environmentally friendly, and inexpensive to produce. β-CD is the most widely used natural CD owing to the suitable size of its inner cavity.We use molecular dynamics (MD) combined with quantum mechanics (QM) method to rank-order binding abilities of CDs and its derivatives with different guest molecules. Explicit solvent NPT molecular dynamics simulations were carried out to sample numerous conformations of CD-ligand complex and the most stable one was extracted from MD trajectory for further free energy calculations. Based on thermodynamic cycle, the total Gibbs free energy change due to complexation in aqueous solution was partitioned into two parts, i.e. the contribution due to the inclusion effect in vacuum and that due to the solvation effect in water. We tested this approach on β-CD and 2,6-dimethyl-β-CD, with various guest molecules. Despite the approximate nature of our model, the resulting affinity rank-ordering for both CD systems correctly matched that from experimental measurements.