Structural background of cyclodextrin-protein interactions

Cyclodextrins are cyclic oligosaccharides with the shape ofa hollow truncated cone. Their exterior is hydrophilic and theircavity is hydrophobic, which gives cyclodextrins the abilityto accommodate hydrophobic molecules/moieties in the cavity.This special molecular arrangement accounts for the varietyof beneficial effects cyclodextrins have on proteins, whichis widely used in pharmacological applications. We have studiedthe interaction between ß-cyclodextrin and four non-carbohydrate-bindingmodel proteins: ubiquitin, chymotrypsin inhibitor 2 (CI2), S6and insulin SerB9Asp by NMR spectroscopy at varying structuraldetail. We demonstrate that the interaction of ß-cyclodextrinand our model proteins takes place at specific sites on theprotein surface, and that solvent accessibility of those sitesis a necessary but not compelling condition for the occurrenceof an interaction. If this behaviour can be generalized, itmight explain the wide range of different effects of cyclodextrinson different proteins: aggregation suppression (if residuesresponsible for aggregation are highly solvent accessible),protection against degradation (if point of attack of a proteaseis sterically ‘masked’ by cyclodextrin), alterationof function (if residues involved in function are ‘masked’by cyclodextrin). The exact effect of cyclodextrins on a givenprotein will always be related to the particular structure ofthis protein. Received May 30, 2003; revised October 27, 2003; accepted October 30, 2003