Hydrodynamic Radii of Intrinsically Disordered Proteins Determined from Experimental Polyproline II Propensities

The properties of disordered proteins are thought to depend on intrinsic conformational propensities for polyproline II (PPII) structure. While intrinsic PPII propensities have been measured for the common biological amino acids in short peptides, the ability of these experimentally determined propensities to quantitatively reproduce structural behavior in intrinsically disordered proteins (IDPs) has not been established. Presented here are results from molecular simulations of disordered proteins showing that the hydrodynamic radius (Rh) can be predicted from experimental PPII propensities with good agreement, even when charge-based considerations are omitted. The simulations demonstrate that Rh and chain propensity for PPII structure are linked via a simple power-law scaling relationship, which was tested using the experimental Rh of 22 IDPs covering a wide range of peptide lengths, net charge, and sequence composition. Charge effects on Rh were found to be generally weak when compared to PPII effects on Rh. Results from this study indicate that the hydrodynamic dimensions of IDPs are evidence of considerable sequence-dependent backbone propensities for PPII structure that qualitatively, if not quantitatively, match conformational propensities measured in peptides.Author Summary: Molecular models of disordered protein structures are needed to elucidate the functional mechanisms of intrinsically disordered proteins, a class of proteins implicated in many disease pathologies and human health issues. Several studies have measured intrinsic conformational propensities for polyproline II helix, a key structural motif of disordered proteins, in short peptides. Whether or not these experimental polyproline II propensities, which vary by amino acid type, reproduce structural behavior in intrinsically disordered proteins has yet to be demonstrated. Presented here are simulation results showing that polyproline II propensities from short peptides accurately describe sequence-dependent variability in the hydrodynamic dimensions of intrinsically disordered proteins. Good agreement was observed from a simple molecular model even when charge-based considerations were ignored, predicting that global organization of disordered protein structure is strongly dependent on intrinsic conformational propensities and, for many intrinsically disordered proteins, modulated only weakly by coulombic effects.