Protein surfaces are complex solutes, and protein-protein interactions are specifically mediated by surface motifs that modulate solvation shells in poorly understood ways. We report herein a supramolecular host that is designed to mimic one of the most important recognition motifs that drives protein-protein interactions, the stacked arginine side chain. We show that it binds its guests and displays good selectivity in the highly competitive medium of pure, buffered water. We use a combination of experimental studies of binding and molecular dynamics simulations to build a cohesive picture of how this biomimetic host achieves the feat. The presence of the stacking element next to the guanidinium groups causes a decrease in the number of host-water hydrogen bonds, a decrease in the density of water around the host, and a decrease in water-water hydrogen bonds near the host. Experimental data using mixed organic/aqueous solvent systems confirm that this host relies on the hydrophobic effect in a way that the two control hosts do not. Our simulations and analysis provide detailed information on the linkage between (de)hydration and binding events in water in a way that could be applied to many aqueous supramolecular systems.