Metal Ion Induced Conformational Changes in Peptides: A Putative Mechanism for the Formation of Abnormal Prion Protein Isoforms

Prion diseases are related to the abnormal folding of proteins. The presence of copper(II) binding sites in PrPC has inspired us to investigate means by which metal ions can trigger such structural changes. In particular, we have studied the electrophilic activation of the amide bond by nitrogen coordination. This mechanism leads to significantly lower rotational barriers and therefore to enhanced amide cis-trans isomerization rates. We have characterized a series of model complexes and tertiary amide ligands by x-ray structure analysis. A common motif in our compounds is a pyramidal nitrogen center. The most important result is that the peptide bond can be significantly distorted from planarity without elongation of the C-N-bond. This finding supports the view of other authors that the out-of-plane vibration of the nitrogen atom has only a very shallow energy minimum. With our studies we provide for the first time a quantitative experimental measure for this flexibility of the amide bond which is a fundamental property closely related to the importance of the peptide bond in biology. We have studied the amide bond cis-trans-isomerization in our complexes by temperature dependent dynamic 1H-NMR-spectroscopy. Significantly reduced rotational barriers were observed in all cases with only minor differences between individual complexes. This is a surprising result because it indicates that even a slightly pyramidalized amide group is strongly activated towards cis-trans-isomerization.