Molecular clips functionalized by phosphonate or phosphate groups bind thiamine diphosphate(TPP) and S-adenosylmethionine (SAM) with high affinity in water; both sulfur-based cofactorstransfer organic groups to biomolecules. For TPP, various analytical tools point toward asimultaneous insertion of both heterocyclic rings into the electron-rich clip cavity. Similarly, SAMis also embedded with its sulfonium moiety inside the receptor cavity. This paves the way for enzymemodels and direct interference with enzymatic processes.