Water energy contributions to structural inhomogeneity of curcubit[8]uril

Expulsion of water from cavities on host binding sites can contribute a great deal of energy to binding of ligands. This can be attributed to the gain in entropy as the waters become unstructured. Accounting for such effects in binding free energy calculations greatly improves the prediction accuracy. This effect is likely to also contribute to the structural reorganization of macromolecules. Using molecular dynamics simulation and the recently developed SSTMap suite we investigate the contribution of water thermodynamics to the tendency of curcubit[8]uril to assuming a compacted structure. Hydration site analysis shows that structuring of waters at the cavity of cb8 carries an entropic penalty which was expected to be relieved upon compaction of cb8. A cb8•ligand complex had overall more favorable hydration upon assuming a more compacted structure compared to its more extended counterpart, suggesting that the compaction was due to water expulsion. To investigate whether the same phenomenon would be observed in the cb8 complex alone, simulations were carried in an explicit solvation model, and an implicit solvation model which lacks water structure information. Contrary to expectation, when simulated in the implicit solvation model cb8 is predominantly compacted, and also assumes an overall more compact structure compared to any of the conformations in the explicit water simulation. Simulations in explicit solvent show a wide distribution of states, with the extended conformation being much more populated then the counterpart in the implicit solvent simulation. Taken together, these findings suggest that structural networks of water, when treated explicitly can have a significant impact on the structural reorganization of macromolecules.