Polyglutamine Fibrils: New Insights into Antiparallel β-Sheet Conformational Preference and Side Chain Structure

Abstract

Understanding the structure of polyglutamine (polyQ) amyloid-like fibril aggregates is crucial to gaining insights into the etiology of at least ten neurodegenerative disorders, including Huntington's disease. Here, we determine the structure of D2Q10K2 (Q10) fibrils using ultraviolet resonance Raman (UVRR) spectroscopy and molecular dynamics (MD). Using UVRR, we determine the fibril peptide backbone Ψ and glutamine (Gln) side chain χ3 dihedral angles. We find that most of the fibril peptide bonds adopt antiparallel β-sheet conformations; however, a small population of peptide bonds exist in parallel β-sheet structures. Using MD, we simulate three different potential fibril structural models that consist of either β-strands or β-hairpins. Comparing the experimentally measured Ψ and χ3 angle distributions to those obtained from the MD simulated models, we conclude that the basic structural motif of Q10 fibrils is an extended β-strand structure. Importantly, we determine from our MD simulations that Q10 fibril antiparallel β-sheets are thermodynamically more stable than parallel β-sheets. This accounts for why polyQ fibrils preferentially adopt antiparallel β-sheet conformations instead of in-register parallel β-sheets like most amyloidogenic peptides. In addition, we directly determine, for the first time, the structures of Gln side chains. Our structural data give new insights into the role that the Gln side chains play in the stabilization of polyQ fibrils. Finally, our work demonstrates the synergistic power and utility of combining UVRR measurements and MD modeling to determine the structure of amyloid-like fibrils.

Molecular mechanisms of 33-mer gliadin peptide oligomerisation

“…68 The importance of Q lateral chain in the formation of protofilaments has been highlighted in different amylogenic diseases, including Huntington's disease. 69 Finally, P is known to form loops, which can trigger oligomerisation. By our simulations, we detect that the internal sequence 71 QPQL has a conserved β secondary structure.…”

“…The 33-mer gliadin peptide, LQLQPFPQPQLP 69 YPQPQLP 76 Y PQPQLP 83 YPQPQPF, is a proteolytical resistant fragment of gliadin, which is a dietary protein found in the gluten of wheat, rye, barley and some varieties of oats. 1,2 The incomplete proteolysis of 33-mer in humans was demonstrated by an analysis of human stool and urine, of subjects under glutencontaining diet, by using different ELISA methods.…”

Thermodynamics of Homopeptide Aggregation

“…Evidence suggests that the β -sheet core is most likely anti-parallel as shown in Fig. 1 (25), although parallel cores may also occur (26). The specifics of parallel or anti-parallel do not enter our model since the parameters give the average interaction experienced by each sequence block.…”

Translational Chemistry Meets Gluten‐Related Disorders

“…Moreover, it is known that glutamine residues can interact through complementary hydrogen bonding, in addition to the aforementioned hydrophobic effect . Glutamine (Q) can link β strands together into β sheets by a network of hydrogen bonds between the amide groups of the chain and the polar side chains . The importance of the Q lateral chain in the formation of protofilaments has been highlighted in different amylogenic diseases, including Huntington's disease .…”