The roles of side chain and backbone in protein structure probed with glycine- and sarcosine-rich synthetic leucine zipper peptides

Abstract

The protein folding problem has long been a formidable challenge. Here we present a synthetic natural motif approach that exploits small preexisting structural models for the dissection of forces important in protein folding. An example for this approach is shown in the modification of a 31-residue leucine zipper peptide with the helix-breaking amino acid glycine and the hydrogen bond-breaking imino acid sarcosine. Circular dichroism and NMR experiments have shown that the glycine-modified leucine zipper peptide adopts a stable helical conformation similar to the native conformation while the sarcosine-modified leucine zipper peptide adopts a random coil conformation. These results provide valuable insight into the current controversy over the relative importance of long-range side chain-side chain interactions versus local backbone interactions in protein structure and suggest that the natural motif strategy may represent a useful model to study protein folding.