title: Intrinsic α helix propensities compact hydrodynamic radii in intrinsically disordered proteins.
abstract: Proteins that lack tertiary stability under normal conditions, known as intrinsically disordered, exhibit a wide range of biological activities. Molecular descriptions for the biology of intrinsically disordered proteins (IDPs) consequently rely on disordered structural models, which in turn require experiments that assess the origins to structural features observed. For example, while hydrodynamic size is mostly insensitive to sequence composition in chemically denatured proteins, IDPs show strong sequence-specific effects in the hydrodynamic radius (Rh) when measured under normal conditions. To investigate sequence-modulation of IDP Rh, disordered ensembles generated by a hard sphere collision model modified with a structure-based parameterization of the solution energetics were used to parse the contributions of net charge, main chain dihedral angle bias, and excluded volume on hydrodynamic size. Ensembles for polypeptides 10-35 residues in length were then used to establish power-law scaling relationships for comparison to experimental Rhfrom 26 IDPs. Results showed the expected outcomes of increased hydrodynamic size from increases in excluded volume and net charge, and compaction from chain-solvent interactions. Chain bias representing intrinsic preferences for α helix and polyproline II (PPII), however, modulated Rhwith intricate dependence on the simulated propensities. PPIIpropensities at levels expected in IDPs correlated with heightened Rhsensitivity to even weak α helix propensities, indicating bias for common (φ, ψ) are important determinants of hydrodynamic size. Moreover, data show that IDP Rhcan be predicted from sequence with good accuracy from a small set of physicochemical properties, namely intrinsic conformational propensities and net charge. Proteins 2017; 85:296-311. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas.
authors.forename: Lance R
authors.initials: LR
authors.lastname: English
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas.
authors.forename: Erin C
authors.initials: EC
authors.lastname: Tilton
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Ricard
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Whitten
mesh_terms: D006801:Humans; D057446:Hydrodynamics; D064267:Intrinsically Disordered Proteins / Q000737:chemistry*; D000072756:Protein Conformation, alpha-Helical; D000072417:Protein Domains; D017510:Protein Folding; D011498:Protein Precursors / Q000737:chemistry*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry*; D055672:Static Electricity; D013816:Thermodynamics; D013947:Thymosin / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D064267:Intrinsically Disordered Proteins; D011498:Protein Precursors; C040782:prothymosin alpha; D013947:Thymosin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: dynamic light scattering; net charge; polyproline type II; simulation; size exclusion chromatography