Structural background of cyclodextrin-protein interactions.
Cyclodextrins are cyclic oligosaccharides with the shape of a hollow truncated cone. Their exterior is hydrophilic and their cavity is hydrophobic, which gives cyclodextrins the ability to accommodate hydrophobic molecules/moieties in the cavity. This special molecular arrangement accounts for the variety of beneficial effects cyclodextrins have on proteins, which is widely used in pharmacological applications. We have studied the interaction between beta-cyclodextrin and four non-carbohydrate-binding model proteins: ubiquitin, chymotrypsin inhibitor 2 (CI2), S6 and insulin SerB9Asp by NMR spectroscopy at varying structural detail. We demonstrate that the interaction of beta-cyclodextrin and our model proteins takes place at specific sites on the protein surface, and that solvent accessibility of those sites is a necessary but not compelling condition for the occurrence of an interaction. If this behaviour can be generalized, it might explain the wide range of different effects of cyclodextrins on different proteins: aggregation suppression (if residues responsible for aggregation are highly solvent accessible), protection against degradation (if point of attack of a protease is sterically 'masked' by cyclodextrin), alteration of function (if residues involved in function are 'masked' by cyclodextrin). The exact effect of cyclodextrins on a given protein will always be related to the particular structure of this protein.
Aachmann
F L
FL
Department of Life Sciences, Aalborg University, Sohngaardsholmsvej 49, DK-9000 Aalborg, Denmark.
Otzen
D E
DE
Larsen
K L
KL
Wimmer
R
R
D003505:Cyclodextrins / Q000737:chemistry* / Q000378:metabolism; D003627:Data Interpretation, Statistical; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009154:Mutation; D010455:Peptides / Q000378:metabolism; D010940:Plant Proteins; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D003505:Cyclodextrins; D007328:Insulin; D010455:Peptides; D010940:Plant Proteins; D025801:Ubiquitin; C093336:chymotrypsin inhibitor 2; D019893:Ribosomal Protein S6 Kinases