Role of electrostatic interactions in amyloid β-protein (Aβ) oligomer formation: A discrete molecular dynamics study

Abstract

Pathological folding and oligomer formation of the amyloid β-protein (Aβ) are widely perceived as central to Alzheimer's disease. Experimental approaches to study Aβ self-assembly provide limited information because most relevant aggregates are quasi-stable and inhomogeneous. We apply a discrete molecular dynamics approach combined with a four-bead protein model to study oligomer formation of Aβ. We address the differences between the two most common Aβ alloforms, Aβ40 and Aβ42, which oligomerize differently in vitro. Our previous study showed that, despite simplifications, our discrete molecular dynamics approach accounts for the experimentally observed differences between Aβ40 and Aβ42 and yields structural predictions amenable to in vitro testing. Here we study how the presence of electrostatic interactions (EIs) between pairs of charged amino acids affects Aβ40 and Aβ42 oligomer formation. Our results indicate that EIs promote formation of larger oligomers in both Aβ40 and Aβ42. Both Aβ40 and Aβ42 display a peak at trimers/tetramers, but Aβ42 displays additional peaks at nonamers and tetradecamers. EIs thus shift the oligomer size distributions to larger oligomers. Nonetheless, the Aβ40 size distribution remains unimodal, whereas the Aβ42 distribution is trimodal, as observed experimentally. We show that structural differences between Aβ40 and Aβ42 that already appear in the monomer folding, are not affected by EIs. Aβ42 folded structure is characterized by a turn in the C-terminus that is not present in Aβ40. We show that the same C-terminal region is also responsible for the strongest intermolecular contacts in Aβ42 pentamers and larger oligomers. Our results suggest that this C-terminal region plays a key role in the formation of Aβ42 oligomers and the relative importance of this region increases in the presence of EIs. These results suggest that inhibitors targeting the C-terminal region of Aβ42 oligomers may be able to prevent oligomer formation or structurally modify the assemblies to reduce their toxicity. © 2007 by the Biophysical Society.