PrP106-126 is located within the important domain concerning membrane related conformational conversion of human Prion protein (from cellular isoform PrPC to scrapie isoform PrPSc). Recent advances reveal that the pathological and physicochemical properties of PrP106-126 peptide are very sensitive to its N-terminal amidation, however, the detailed mechanism remains unclear. In this work, we studied the interactions of the PrP106-126 isoforms (PrP106-126(CONH2) and PrP106-426(COOH)) with the neutral lipid bilayers by atomic force microscopy, surface plasmon resonance and fluorescence spectroscopy. The membrane structures were disturbed by the two isoforms in a similarly stepwise process. The distinct morphological changes of the membrane were characterized by formation of semi-penetrated defects and sigmoidal growth of flat high-rise domains on the supported lipid bilayers. However, PrP106-126(COOH) displayed a higher peptide-lipid binding affinity than PrP106-126(CONH2) (similar to 2.9 times) and facilitated the peptide-lipid interactions by shortening the lag time. These results indicate that the C-terminal amidation may influence the pathological actions of PrP106-126 by lowering the interaction potentials with lipid membranes. (c) 2008 Elsevier Inc. All rights reserved.