| Abstract
| - Understanding the fundamental principles that govern the binding of a guest molecule to its host and accurateprediction of the binding mode of the guest/host complex are important goals in guest−host chemistry andhave implications in structure-based drug design. In this paper, we report our computational investigation ofbenzyl alcohol (the guest) binding to β-cyclodextrin (the host) in the presence of explicit water moleculesusing both the self-guided molecular dynamics (SGMD) simulation method and conventional MD simulationmethod. The simulation system was constructed in such a way that 6 guest and 1 host molecules were solvatedin a cubic water box of 35 Å in dimension. Two SGMD simulations were performed for 1.5 ns and 2.5 nsat 300 K, respectively, starting from uncomplexed, two totally different initial configurations of the guestand host molecules. In both SGMD simulations, competitive and reversible binding of the guest moleculesto the host is observed. Analysis of the simulation trajectories showed that one major complexed conformationalcluster 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 bindingforces showed that the burial of the phenyl group in the cavity of β-cyclodextrin, but not the hydrogen bondinginteraction between the guest and the host, is the major change for binding, suggesting that that hydrophobicinteraction may be responsible for the formation of the complex. To verify the predictions made by the SGMDmethod, we performed two 12.5 ns conventional MD simulations with the same initial setup and same conditionsas for the two SGMD simulation runs. Additionally, we have performed a 10 ns long conventional MDsimulation starting from the crystal structure of the complex. The MD simulations predicted major solutionbinding modes similar to those identified through the SGMD simulations, including the conformational clusterthat is essentially the same as that found in the X-ray structure. Our studies showed that the SGMD methodis an efficient way to study competitive and reversible binding of guest molecules to their hosts in aqueoussolution. The SGMD method may also be useful to study the binding of drug molecules to their marcomoleculartargets.
|
