Secondary Structure

The secondary structure of a peptide or protein refers to local folding motifs stabilized primarily by hydrogen bonds between backbone atoms (C=O carbonyls and N-H amides), independently of side chain nature. It is the second level of organization described by Linderstrøm-Lang, between primary structure (sequence) and tertiary structure (overall 3D fold).

The three canonical motifs are the α helix (3.6 residues per turn, 5.4 Å pitch, hydrogen bonds between residue i and i+4), the β sheet (extended strands with inter-strand hydrogen bonds, parallel or antiparallel), and β turns (4-residue direction reversals, often enriched in glycine, proline, and polar amino acids). Minor structures include the 3-10 helix, π helix, Ω loops, and intrinsically disordered regions (IDRs) that lack a defined structure in solution.

The propensity of an amino acid to adopt each motif depends on its physicochemical properties: alanine, leucine, glutamate, and methionine favor α helix; valine, isoleucine, phenylalanine, and tyrosine favor β sheet; proline breaks helices and is often found in turns; glycine, being flexible, permits direction reversals.

Experimental characterization mainly uses circular dichroism (CD) in the far UV (190-250 nm), which gives distinct spectral signatures for each motif, infrared spectroscopy (amide I around 1650 cm⁻¹), NMR (NOE, ³J couplings), and X-ray crystallography. Predictive tools (DSSP, STRIDE, recent AlphaFold-based algorithms) allow automatic annotation of known structures.

In peptide design, secondary structure stabilization is a major lever of activity: stapled peptides, bicyclized peptides, and analogs with α-methylated or β-amino acids rigidify an active helix and increase affinity, peptidase resistance, and selectivity. Predictable local folding is therefore essential for rational design.