Abstract
The properties of disordered proteins are thought to depend on intrinsic conformational propensities for polyproline II (PP II) structure. While intrinsic PP II 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 (R h) can be predicted from experimental PP II propensities with good agreement, even when charge-based considerations are omitted. The simulations demonstrate that R h and chain propensity for PP II structure are linked via a simple power-law scaling relationship, which was tested using the experimental R h of 22 IDPs covering a wide range of peptide lengths, net charge, and sequence composition. Charge effects on R h were found to be generally weak when compared to PP II effects on R h. Results from this study indicate that the hydrodynamic dimensions of IDPs are evidence of considerable sequence-dependent backbone propensities for PP II structure that qualitatively, if not quantitatively, match conformational propensities measured in peptides.
Highlights
Many proteins, and protein domains, that perform critical biological tasks have disordered structures under normal solution conditions [1,2,3]
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
Summary
Protein domains, that perform critical biological tasks have disordered structures under normal solution conditions [1,2,3]. A number of issues with that hypothesis, are apparent It has not been established if PPII propensities measured in short peptide models of the unfolded states of proteins [17,18,19] translate to IDPs. It could be that PPII propensities are negligible and unimportant in IDP systems. Methods capable of separating the impact of weak to possibly strong local conformational propensities and charge-charge interactions in the context of flexible and disordered protein structures have not been demonstrated, but are required for testing any potential interdependence
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