(225a) Water Orientation and Dynamics in Cavitand Pockets

Hydrophobic interactions drive the binding of nonpolar ligands to the oily pockets of proteins and supramolecular species in aqueous solution. Thus, the wetting of host pockets is expected to play a critical role in determining the thermodynamics of guest binding. This however requires a good understanding of the properties of water molecules in such hosts since they can be very different from those in the bulk. This is expected to unveil the role of water in guiding solvent specific interactions between host and guest species in solution. In this work, we use molecular simulations to examine the structure of water in the pockets of deep-cavity cavitands and the kinetics of their filling and emptying. Deep-cavity cavitands are a class of water-soluble, bowl-shaped supramolecular host species possessing a nonpolar guest binding pocket that is approximately 8 Å deep with a portal opening approximately 8 Å wide. Here, we employed the non-functionalized parent cavitand octa-acid, tetra-endo-methyl octa-acid (which differs from the parent by four methyl groups oriented inward towards the pocket) and positand (which differs from the parent by replacing the acid groups with quaternary ammoniums). Based on the water occupation state of each cavity, we mapped out via graph analysis the different water structures using hydrogen bonding as connection between nodes. This enabled us to distinguish the water distribution and orientation in the different cavitands as well as to determine the regimes and stability of the structures. Our results also show that empty pockets are especially long lived compared to their filled counterparts which suggests that the emptying of hydrophobic pockets will play a key role in binding kinetics.