Step-wise formation of helical structure and side-chain packing in a peptide from scorpion neurotoxin support hierarchic model of protein folding.

The mechanism of protein folding has been the subject of extensive investigation during the last decade, both because of its academic challenge and because of its relation to many diseases which are known to occur due to misfolding of proteins. In this context, we report here a systematic investigation on the step-wise formation of a helical structure by the addition of hexafluoroacetone, in a 14-residue peptide derived from a part of the scorpion neurotoxin protein. The NMR and circular dichroism results indicate that the peptide has an inherent propensity for helix formation and this is limited to the internal few residues in aqueous solution. With the addition of the fluorosolvent, the helical content progressively increases and spans the whole sequence. This is accompanied by concomitant packing of the side chains. These results provide support to the so-called hierarchic model of protein folding which dictates that the local sequence determines the secondary structures in the protein and the side chains play an important role in this process.