Secondary Structures of Proteins and Peptides in Amphiphilic Environments (A Review)

Many peptides and proteins that act at lipid-water interfaces assume a unique amphiphilic secondary structure which is induced by the anisotropy of the interface. By using synthetic peptides in which these inducible amphiphilic structures have been optimized, one can show that the amphiphilic α helix is a functional determinant of representative apolipoproteins, peptide toxins, and peptide hormones. By increasing the amphiphilicity of the structurally important regions of the molecule, one can enhance the biological activity of the peptide even beyond that of the naturally occurring polypeptide. It is proposed that rigid amphiphilic secondary structures such as α helix, β sheet, or π helix will be found in most medium-sized peptides acting at membranes and lipid-water interfaces. The applications of the design concept presented in this article to the preparation of effective models for three different categories of biologically active peptides--an apolipoprotein, a peptide toxin, and a hormone--have been presented. The maintenance or increase in activity when the natural amino acid sequence is replaced by an idealized amphiphilic secondary structure shows that these amphiphilic structures indeed represent the active conformation of the molecule. As a rule, these structures are not dominant when the peptide is dissolved in water but they are induced either by an amphiphilic surface or by an amphiphilic self-association to form peptide micelles. The importance of amphiphilic secondary structures in the surface-active peptides has been explored primarily with reference to the amphiphilic α helix because this structure is most readily accessible to us. However, it should be emphasized that the α -helix is only one type of secondary structure that can have amphiphilic character. Our model studies fully support the proposal that, for medium-size peptides without intrachain crosslinks, an amphiphilic environment can induce a single, specific, secondary structure. By analogy, one would predict that any asymmetric environment such as an electric field, a phase boundary, or even the surface of a macromolecule or of a macromolecular aggregate would induce secondary structures in a peptide with the appropriate amino acid side chains. When the locus of action of a medium-size peptide is a membrane or a lipoprotein, the amphiphilic character is the dominant factor of the environment. It is then quite likely that all membrane-directed hormones and regulators will contain