What makes the guanidinium cation so special?

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When studying the effect of ions on the stability of proteins, simple inorganic cations follow an important rule of thumb: the higher the surface charge density of the cation the stronger the ion destabilizes proteins in solution. However, the rather bulky, organic guanidinium cation (Gdm+), having a low surface charge density, is amongst the most effective protein denaturants. Thus, Gdm+ is a prominent exception in the Hofmeister series. In recent years it became apparent that this exceptional effect of Gdm+ on proteins cannot be explained from bulk properties of aqueous guanidinium electrolytes, but must be related to the specific interaction of Gdm+ with proteins.Indeed, computer simulations suggest specific interaction of Gdm+ with model proteins. However, to date the exact mechanism how Gdm+ interacts with proteins is controversially discussed. It has been suggested that Gdm+ ions bind to the peptide backbone, interact with the positively or negatively charged protein side-chains, or cover hydrophobic fragments of the proteins. Each of these interaction mechanisms is claimed to lead to the unfolding of the protein.We will study the interaction of Gdm+ with small model proteins experimentally and test the different scenarios mentioned above. We will determine the binding strength of Gdm+ to hydrophobic moieties, charged side chains, and to the amide backbone. This will reveal the predominant unfolding mechanism and what makes the guanidinium cation such an efficient protein denaturant.