Influence of Local and Residual Structures on the Scaling Behavior and Dimensions of Unfolded Proteins

TL;DR

This study uses Monte Carlo simulations to explore how local structures like alpha helices and PPII influence the size and dimensions of unfolded proteins, reconciling conflicting experimental observations.

Contribution

It demonstrates how specific local structures affect unfolded protein dimensions, providing a unified understanding of experimental data on denatured proteins.

Findings

20% alpha helix content matches experimental radii of gyration

High alpha helix content (87%) explains unfolded state dimensions

PPII content increases chain expansion but is not the dominant conformation

Abstract

Although recent spectroscopic studies of chemically denatured proteins hint at significant nonrandom residual structure, the results of extensive small angle X-ray scattering studies suggest random coil behavior, calling for a coherent understanding of these seemingly contradicting observations. Here, we report the results of a Monte Carlo study of the effects of two types of local structures, a helix and Polyproline II (PPII) helix, on the dimensions of random coil polyalanine chains viewed as a model of highly denatured proteins. With an alpha helix content of 20%, corresponding to the Ramachandran probability of being in the helical basin, experimentally observed radii of gyration are recovered. Experimental radii are similarly recovered at an a helix content of 87%, providing an explanation for the previously puzzling experimental finding that the dimensions of the highly helical methanol-induced unfolded state are experimentally indistinguishable from those of the helix-poor urea-unfolded state. In contrast, the radius of gyration increases monotonically with increasing PPII content, and is always more expanded than the dimensions observed experimentally. These results suggest that PPII is unlikely the sole, dominant preferred conformation for unfolded proteins.