Using Unnatural Side-Chain Interactions

Baldwin and co-workers [4] have made a pioneering contribution in this area. They demonstrated that short (11-15 residues) alanine-rich peptides (such as 1), having several glu-lys salt bridges adopt a stable monomeric a-helix structure in solution. 

This strategy is somewhat reminescent of the biological folding pathways of natural polypeptides that use selective interactions with effectors (Ca2+, chaperone proteins, etc.) to start the nucleation of the secondary structures [5] and has been used successfully to prepare well defined peptide nanostructures by several groups. 

Hopkins and co-workers [6] have used the selective complexation of transition metals by two distant EDTA modified amino acids to stabilize the a-helical conformation of peptides 2 and 3 (Fig. 3). The results were particularly impressive in the case of 3 where the helicity increased from 0 to about 80% upon complexation of Cd2 4 ions. Along the same lines, Ghadiri and coworkers [7] reported the important stabilization of the helical conformation of 4 and 5 by the formation of selective metal complexes (Ru2+, Zn2+, Cu2+, and Cd2+) involving either two imidazoles of histidines or one imidazole and one thiol from a cysteine separated by three amino acids (I, 1 + 4) (Fig. 4). They also reported that peptide 4 is Cd2+-selective and that the helical conformation of the inert Ru2+ complex of 5 is remarkably stable. For instance, it has a melting point 25 °C higher than the uncomplexed peptide in water. 

Another interesting approach to solve the problem of preparing peptide nanostructures with predictable solution conformations has been taken by Gellman and Dado [8]. They designed an 18-residue peptide 6 that could have 

A similar peptidic conformational switch was developed by Mutter and Hersperger [9]. In that work, they showed that the 15-residue peptide 7 could have its conformation modulated by the polarity of the solvent (Fig. 6). Indeed, peptide 7 was shown to adopt an a-helical structure in trifluoroethanol and 

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Fig. 2. Schematic representation of the use of unnatural side chain interactions to alter the conformational equilibrium towards a more ordered structure. The binding of a specific guest displaces the equilibrium towards a conformation that orients the binding side chains complementary to the geometry of the guest...

Since reductive S-alkylation of disulfide bonds introduces unnatural amino acid side chains into the protein and, therefore, cannot serve as a useful model for nutritional and toxicological studies, we initiated systematic studies of effects of thiols on the inhibitory process. Such thiols are expected to interact with inhibitor disulfide bonds via sulfhydryl-disulfide interchange and oxidation reactions (Friedman, 1973). 

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