Are denatured proteins ever random coils?

To polymer chemists, the term random coil means a chain molecule whose backbone coils randomly in three-dimensional space, with a conformation described by the Gaussian probability function (1). To protein chemists, the term random coil carries an added special meaning: the backbone conformation of every amino acid residue, described by its phi, psi pair of backbone angles, is independent of the conformations of neighboring residues. This is Flory's isolated-pair hypothesis (2). If it is valid for denatured proteins in specified solvent conditions, then the random coil protein in these conditions has no structure characteristic of the native protein, which could be used to guide the first steps of the refolding process. Evidently, study of the folding problem would be greatly simplified if conditions could be found in which denatured proteins assume the random coil conformation. In proposing the isolated-pair hypothesis, Flory was motivated by his own experimental analysis of the chain dimensions of some peptides: see especially his later work on poly-l-alanines (3).

Pappu et al. in this issue of PNAS (4) now find that the isolated-pair hypothesis is valid for alanine peptides only within a restricted region of the Ramachandran map, near the β-strand or extended region. For example, steric exclusion by contacts between residues separated by 3–6 peptide bonds is pronounced near the right-hand α-region of the map. The result is to stiffen the peptide chain and reduce the number of possible conformations. Pappu et al. obtain their …