Energetics Underlying Twist Polymorphisms in Amyloid Fibrils

Abstract

Amyloid fibrils are highly ordered protein aggregates associated with more than 40 human diseases. The exact conditions under which the fibrils are grown determine many types of reported fibril polymorphism, including different twist patterns. Twist-based polymorphs display unique mechanical properties in vitro, and the relevance of twist polymorphism in amyloid diseases has been suggested. We present transmission electron microscopy images of Aβ42-derived (amyloid β) fibrils, which are associated with Alzheimer's disease, demonstrating the presence of twist variability even within a single long fibril. To better understand the molecular underpinnings of twist polymorphism, we present a structural and thermodynamics analysis of molecular dynamics simulations of the twisting of β-sheet protofilaments of a well-characterized cross-β model: the GNNQQNY peptide from the yeast prion Sup35. The results show that a protofilament model of GNNQQNY is able to adopt twist angles from -11° on the left-hand side to +8° on the right-hand side in response to various external conditions, keeping an unchanged peptide structure. The potential of mean force (PMF) of this cross-β structure upon twisting revealed that only ∼2kT per peptide are needed to stabilize a straight conformation with respect to the left-handed free-energy minimum. The PMF also shows that the canonical structural core of β-sheets, i.e., the hydrogen-bonded backbone β-strands, favors the straight conformation. However, the concerted effects of the side chains contribute to twisting, which provides a rationale to correlate polypeptide sequence, environmental growth conditions and number of protofilaments in a fibril with twist polymorphisms.

Polymorphic Aβ42 fibrils adopt similar secondary structure but differ in cross-strand side chain stacking interactions within the same β-sheet

“…This finding is credited to the sensitivity of EPR measurements to not only static structure, but also backbone and side chain dynamics. Side chain interactions in the β-sheet have been shown to be a determining factor of fibril twist 25,26 , a feature that is both distinguishing and most recognizable for different fibril polymorphs. While backbone hydrogen bonds always favor flat β-sheets, side chain interactions favor twisted β structures 37 .…”

“…EPR data further revealed that side chains are more tightly packed in agitated Aβ40 fibrils than in quiescent Aβ40 fibrils. The strength of side chain packing interactions may determine the degree of β-sheet twist 25,26 , a distinguishing feature of some Aβ fibril polymorphs.…”

Functionalized Mesoporous Silicas Direct Structural Polymorphism of Amyloid-β Fibrils

“…Previous molecular dynamics (MD) simulations of fragments of amyloidogenic protein sequences (Sup35) have suggested that changes in fibril twisting (cross-over distance) may be due to different charge interactions at the protein's N-and C-termini (80,81). Specifically, with a negative charge at the C-terminus, model proteins adopted the more energetically favorable twisting conformation in MD simulations compared to the fibrils with no cross-over distance, which were less energetically favored (81). These simulation results may explain why the accessible negative surface charge of SBA-15 favors the formation of λ and μ fibrils compared to the ε fibrils that were highly represented in the control, SBA-PEG, and SiMP samples.…”

Molecular dynamics simulation reveals that switchable combinations of β-sheets underlie the prion-like properties of α-synuclein amyloids

“…MD simulation of the αSyn amyloids demonstrated that all the β-sheets incessantly moved in a vibratory manner in narrow spaces, except for β1 and β2 which tended to freely twist and fan ( Supplementary Movie ). Considering the intrinsic twisting tendency [43], it is conceivable that the other β-sheets also share the tendency to twist like β1 and β2. Although they are not allowed to twist freely due to the compact packaging in the Greek-key conformation, even small twists can cause differences in the distances of β-sheets between on the Chain-A side and on the Chain-J side, and consequently differences in structural stabilities because hydrogen bonds or hydrophobic effects are greatly affected by the distances.…”

“…Given the existence of hydrogen bonds and hydrophobic effects between β3, β5 and β7 as revealed by the MD simulation, alterations in those interactions seem the most likely mechanism of the remote effects. In addition, the intrinsic twisting tendency of β-sheets could modulate the interactions because those properties of β-sheets affect each other [43]. The extra inter-layer hydrogen bonds of homo-A53T amyloid between Thr53 and Gly73 and/or Val74 suggest more intimate β3-β5 interactions ( Fig 3 ), which also explain the alterations of β-sheet propensities in the residues of β5.…”