We find, through atomistic molecular dynamics simulation of native cyclodextrins (CDs) in water, that although the outer surface of a CD appears like a truncated cone, the inner cavity resembles a conical hourglass because of the inward protrusion of the glycosidic oxygens. Furthermore, the conformations of the constituent α-glucose molecules are found to differ significantly from a free monomeric α-glucose molecule. This is the first computational study that maps the conformational change to the preferential hydrogen bond donating capacity of one of the secondary hydroxyl groups of CD, in consensus with an NMR experiment. We have developed a simple and novel geometry-based technique to identify water molecules occupying the nonspherical CD cavity, and the computed water occupancies are in close agreement with the experimental and density functional theory studies. Our analysis reveals that a water molecule in CD cavity loses out about two hydrogen bonds and remains energetically frustrated but possesses higher orientational degree of freedom compared to bulk water. In the context of CD-drug complexation, these imply a nonclassical, that is, enthalpically driven hydrophobic association of a drug in CD cavity.

Water structure in aqueous osmolyte solutions, deduced from the slight alteration in the water−water radial distribution function, the decrease in water−water hydrogen bonding, and tetrahedral ordering based only on the orientation of nearest water molecules derived from the molecular dynamics simulations, appears to have been perturbed. A careful analysis, however, reveals that the hydrogen bonding and the tetrahedral ordering around a water molecule in binary solutions remain intact as in neat water when the contribution of osmolyte−water interactions is appropriately incorporated. Furthermore, the distribution of the water binding energies and the water excess chemical potential of solvation in solutions are also pretty much the same as in neat water. Osmolytes are, therefore, well integrated into the hydrogen-bond network of water. Indeed, osmolytes tend to preferentially hydrogen bond with water molecules and their interaction energies are strongly correlated to their hydrogen-bonding capability. The graph network analysis, further, illustrates that osmolytes act as hubs in the percolated hydrogen-bond network of solutions. The degree of hydrogen bonding of osmolytes predominantly determines all of the network properties. Osmolytes like ethanol that form fewer hydrogen bonds than a water molecule disrupt the water hydrogen-bond network, while other osmolytes that form more hydrogen bonds effectively increase the connectivity among water molecules. Our observation of minimal variation in the local structure and the vitality of osmolyte−water hydrogen bonds on the solution network properties clearly imply that the direct interaction between protein and osmolytes is solely responsible for the protein stability. Further, the relevance of hydrogen bonds on solution properties suggests that the hydrogen-bonding interaction among protein, water, and osmolyte could be the key determinant of the protein conformation in solutions.