Intrinsically Disordered Protein Regions Modeled as Isolated Entities Commonly Adopt Ensembles of Collapsed, Globular Conformations

Intrinsically disordered proteins (IDPs) adopt an ensemble of conformations under native physiological conditions. Despite their lack of folded structure, they perform important physiological functions and are predicted to constitute around 30% of eukaryotic proteomes. The success of disorder prediction using a protein's primary structure suggests that the propensity for disorder is encoded in the amino acid sequence. Previously, we found that net charge per residue segregates IDP sequences along a globule-to-coil transition and speculated that the polymeric characters of an IDP conformational ensemble could be predicted using only physicochemical properties derived from its amino acid composition. We tested these predictions by studying over 100 intrinsically disordered regions (IDRs) extracted from the DisProt database using atomistic Metropolis simulations in ABSINTH implicit solvent. For most of these IDRs, which exhibit low absolute net charge per residue, simulation results agreed with predictions of a collapsed, globular conformational ensemble. However, the expected swelling with higher absolute net charge per residue was only observed for positively charged IDRs. Here, we explore possible mechanisms and provide a physicochemical basis for the asymmetric behavior of sequences rich in anionic residues (aspartate and glutamate) versus those rich in cationic residues (arginine and lysine). Additionally, we discuss the functional consequences of sequence patterning in IDPs.Supported by grants 5T32GM008802 from the NIH National Institute of General Medical Sciences and MCB 0718924 from the National Science Foundation.