An accurate model of polyglutamine

Abstract

Polyglutamine repeats in proteins are highly correlated with amyloid formation and neurological disease. To better understand the molecular basis of glutamine repeat diseases, structural analysis of polyglutamine peptides as soluble monomers, oligomers, and insoluble amyloid fibrils is necessary. In this study, fluorescence resonance energy transfer (FRET) experiments and molecular dynamics simulations using different theoretical models of polyglutamine were conducted. This study demonstrates that a previously proposed simple C(α)C(β) model of polyglutamine, denoted as FCO, accurately reproduced the present FRET results and the results of previously published FRET, triplet-state quenching, and fluorescence correlation studies. Other simple C(α)C(β) models with random coil and extended β-strand parameters, and all-atom models with parm96 and parm99SB force fields, did not match the FRET result well. The FCO is an intrinsically disordered model with a high-effective persistence length producing extended peptides at short lengths (Q(N) < 10). Because of an increasing number of attractive Q-Q interactions at longer lengths, the FCO model becomes increasingly more compact at lengths between Q(N) ∼ 10-16 and is as compact as many folded proteins at Q(N) > 16.

Backbone Engineering within a Latent β-Hairpin Structure to Design Inhibitors of Polyglutamine Amyloid Formation

“…6b), which confirms a very low upper limit to β-hairpin content of less than 1% (Results). These data underscore a central problem for the “toxic monomer” hypothesis for polyQ toxicity: the compact coil nature of polyQ, which is the favored form of the monomer for sequences from Q 16 51, 52 to Q 53 50 , is highly resistant to engaging any stable, regular secondary structure, including a β-hairpin. Previous solution NMR studies already demonstrated the absence of detectible β-structure in simple monomeric polyQ peptides before they become incorporated into amyloid 53-55 .…”

“…Since the apparent monomeric nucleation equilibrium constant K N* for polyQ amyloid formation is typically in the range of 10 −10 to 10 −14 21, 48 , the 10-100 fold improvement in the equilibrium constant for β-hairpin formation expected from β-hairpin inducing mutations 21, 26 would be insufficient to allow detection of these β-hairpin forms by conventional spectroscopy. The special resistance of polyQ to acquiring regular folded monomeric states may be a consequence of a conformational ensemble dominated by robust, fluctuating side chain-main chain H-bonding 49 , a factor that also may be responsible for the compact coil structures reported for polyQ sequences longer than about Q 15 50-52 . In spite of the resistance of polyQ peptides to accessing stable β-hairpin conformations in the monomer ensemble, these peptides – mutated or not – readily access such conformations when incorporated into the amyloid fibril core 24 .…”

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

“…59, 99–103104 Based on a series of circular dichroism (CD) and NMR experiments, pure polyQ monomers, both below and above the typical pathological threshold in length, are predominately disordered with little difference in secondary structure as a function of polyQ length. 23, 64, 67, 105–108 With these pure polyQ peptides, NMR studies did not detect distinct monomeric intermediates prior to aggregation into fibrils.…”

Aggregation Kinetics of Interrupted Polyglutamine Peptides

“…19 This length-dependent pattern can be explained by considering that a preference for β-strand dihedrals, which tend to extend the polypeptide chain, competes with longer-range attractive contacts, which tend to collapse the chain and become more significant as the number of glutamines increases. 28 …”