Competitive and reversible binding of a guest molecule to its host in aqueous solution through molecular dynamics simulation:: Benzyl alcohol/β-cyclodextrin system

Understanding the fundamental principles that govern the binding of a guest molecule to its host and accurate prediction of the binding mode of the guest/host complex are important goals in guest-host chemistry and have implications in structure-based drug design. In this paper, we report our computational investigation of benzyl alcohol (the guest) binding to beta-cyclodextrin (the host) in the presence of explicit water molecules using both the self-guided molecular dynamics (SGMD) simulation method and conventional MD simulation method. The simulation system was constructed in such a way that 6 guest and I host molecules were solvated in a cubic water box of 35 Angstrom in dimension. Two SGMD simulations were performed for 1.5 ns and 2.5 ns at 300 K, respectively, starting from uncomplexed, two totally different initial configurations of the guest and host molecules. In both SGMD simulations, competitive and reversible binding of the guest molecules to the host is observed. Analysis of the simulation trajectories showed that one major complexed conformational cluster is in good agreement with the complex structure determined using the X-ray diffraction. In addition, several other major binding modes were also identified in aqueous solution. Investigation of the binding forces showed that the burial of the phenyl group in the cavity of beta-cyclodextrin, but not the hydrogen bonding interaction between the guest and the host, is the major change for binding, suggesting that that hydrophobic interaction may be responsible for the formation of the complex. To verify the predictions made by the SGMD method, we performed two 12.5 ns conventional MD, simulations with the same initial setup and same conditions as for the two SGMD simulation runs. Additionally, we have performed a 10 ns long conventional MD simulation starting from the crystal structure of the complex. The MD simulations predicted major solution binding modes similar to those identified through the SGMD simulations, including the conformational cluster that is essentially the same as that found in the X-ray structure. Our studies showed that the SGMD method is an efficient way to study competitive and reversible binding of guest molecules to their hosts in aqueous solution. The SGMD method may also be useful to study the binding of drug molecules to their marcomolecular targets.