2025/01/30 by Jeffry Setiadi, Frank Biedermann, Werner M. Nau +1 · 1 voice
Chemistry · #Advanced NMR Techniques and Applications #Crystallography and molecular interactions #Supramolecular Chemistry and Complexes
paper · pdf · doi:10.26434/chemrxiv-2025-02wrf
openalex publication_date 2025/01/30 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/14
The role of water displacement in noncovalent binding has been debated in the fields of supramolecular chemistry and drug design. We use molecular dynamics simulations of idealized host-guest systems to address the long-standing controversy of whether water is merely a bystander or an actual driver of noncovalent binding in aqueous solution. To isolate hydration effects, we consider a pseudo-hard-sphere guest binding to a series of cucurbit[8]uril-based host models whose energetic interactions with water vary widely. The computed free energy cost of displacing water from binding sites ranges from 0 to +37 kcal/mol, strongly influencing binding affinities. However, neither water density nor excess chemical potential reliably indicates the thermodynamic favorability of cavity water. These results support the concept that "unfavorable" binding site water contributes to high-affinity binding and resolve the paradox of stable but thermodynamically unfavorable cavity water. This work provides insights into the nature of the hydrophobic effect in molecular recognition and offers a framework for understanding water's role in binding across various host-guest and protein-ligand systems.