Random-coil behavior and the dimensions of chemically unfolded proteins

TLDR

Spectroscopic studies suggest some proteins retain residual structure even under strong denaturation, yet viscosity, hydrodynamic, and SAXS measurements indicate that most chemically denatured proteins follow random‑coil scaling with polypeptide length. The study aims to resolve this discrepancy by extending the length range of denatured‑state radii of gyration and reexamining proteins that reportedly deviate from expected scaling. The authors measured radii of gyration for 28 crosslink‑free, prosthetic‑group‑free chemically denatured polypeptides spanning 16–549 residues, fitting the data to a power‑law relationship with polymer length. Only two of the 28 polypeptides deviated from the power law; the remaining 26 fit a 0.598 ± 0.028 exponent (r² = 0.988), matching the 0.588 excluded‑volume random‑coil prediction, indicating that most chemically denatured proteins have dimensions indistinguishable from random coils.

Abstract

Spectroscopic studies have identified a number of proteins that appear to retain significant residual structure under even strongly denaturing conditions. Intrinsic viscosity, hydrodynamic radii, and small-angle x-ray scattering studies, in contrast, indicate that the dimensions of most chemically denatured proteins scale with polypeptide length by means of the power-law relationship expected for random-coil behavior. Here we further explore this discrepancy by expanding the length range of characterized denatured-state radii of gyration ( R G ) and by reexamining proteins that reportedly do not fit the expected dimensional scaling. We find that only 2 of 28 crosslink-free, prosthetic-group-free, chemically denatured polypeptides deviate significantly from a power-law relationship with polymer length. The R G of the remaining 26 polypeptides, which range from 16 to 549 residues, are well fitted ( r 2 = 0.988) by a power-law relationship with a best-fit exponent, 0.598 ± 0.028, coinciding closely with the 0.588 predicted for an excluded volume random coil. Therefore, it appears that the mean dimensions of the large majority of chemically denatured proteins are effectively indistinguishable from the mean dimensions of a random-coil ensemble.