Small molecule host-guest complexes have traditionally provided model systems for biological ligand recognition. Nonetheless, direct extrapolation of these results is precluded by the comparative simplicity of these supramolecular assemblies. If energetic behavior analogous to small molecule host-guest chemistry exists, it is unclear how this would manifest for protein-small molecule interactions. To answer this question, we employ the retinol/serum retinol binding protein (sRBP) system as an analogue of a classical host-guest complex. Using a combination of molecular dynamics simulations and free energy methods, we decompose the potential of mean force for retinol unbinding from the sRBP into constituent interactions. Our calculations reveal an unexpected mechanism of host-guest complexation. Desolvation is sufficient to drive formation of an intermediate binding state; however, a combination of electrostatic and van der Waals interactions pull the intermediate into a stable configuration. Association is accompanied by a change in the conformational flexibility of the portal domains of sRBP and subsequent stiffening of the holo sRBP, reflecting an order-disorder transition in the protein.