Amyloid fibrils are highly ordered protein aggregates associated with more than 40 human diseases. The exact conditions in 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 degrees on the left-handed side to +8 degrees on the right-handed side in response to various external conditions while keeping an unchanged peptide structure. The potential of mean force (PMF) of this cross-β structure upon twisting revealed that only ~2 kB¬T 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, favours 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.
|Tijdschrift||The Journal of Physical Chemistry. B: Materials, Surfaces, Interfaces, & Biophysical|
|Nummer van het tijdschrift||3|
|Status||Published - 2018|