title: Fluorescence correlation spectroscopy shows that monomeric polyglutamine molecules form collapsed structures in aqueous solutions.
abstract: We have used fluorescence correlation spectroscopy measurements to quantify the hydrodynamic sizes of monomeric polyglutamine as a function of chain length (N) by measuring the scaling of translational diffusion times (tau(D)) for the peptide series (Gly)-(Gln)(N)-Cys-Lys(2) in aqueous solution. We find that tau(D) scales with N as tau(o)N(nu) and therefore ln(tau(D)) = ln(tau(o)) + nuln(N). The values for nu and ln(tau(o)) are 0.32 +/- 0.02 and 3.04 +/- 0.08, respectively. Based on these observations, we conclude that water is a polymeric poor solvent for polyglutamine. Previous studies have shown that monomeric polyglutamine is intrinsically disordered. These observations combined with our fluorescence correlation spectroscopy data suggest that the ensemble for monomeric polyglutamine is made up of a heterogeneous collection of collapsed structures. This result is striking because the preference for collapsed structures arises despite the absence of residues deemed to be hydrophobic in the sequence constructs studied. Working under the assumption that the driving forces for collapse are similar to those for aggregation, we discuss the implications of our results for the thermodynamics and kinetics of polyglutamine aggregation, a process that has been implicated in the molecular mechanism of Huntington's disease.
authors.affiliation: Department of Biomedical Engineering, Washington University, One Brookings Drive, Box 1097, St. Louis, MO 63130, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Crick
authors.forename: Murali
authors.initials: M
authors.lastname: Jayaraman
authors.forename: Carl
authors.initials: C
authors.lastname: Frieden
authors.forename: Ronald
authors.initials: R
authors.lastname: Wetzel
authors.forename: Rohit V
authors.initials: RV
authors.lastname: Pappu
mesh_terms: D002942:Circular Dichroism; D006801:Humans; D006816:Huntington Disease / Q000209:etiology; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D016014:Linear Models; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000633:toxicity; D017433:Protein Structure, Secondary; D012996:Solutions; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics; D014867:Water
chemical_list: D010455:Peptides; D012996:Solutions; D014867:Water; C097188:polyglutamine