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Role of Electrostatic Interactions in Amyloid ß-Protein (Aß) Oligomer Formation: A Discrete Molecular Dynamics Study

Sijung Yun ^*, B. Urbanc ^*, L. Cruz ^*, G. Bitan , D. B. Teplow  and H. E. Stanley ^*

^* Center for Polymer Studies, Department of Physics, Boston University, Boston, Massachusetts; and Department of Neurology, David Geffen School of Medicine, Brain Research Institute and Molecular Biology Institute, University of California, Los Angeles, California

Correspondence: Address reprint requests to B. Urbanc, E-mail: brigita{at}bu.edu.

Pathological folding and oligomer formation of the amyloid ß-protein (Aß) are widely perceived as central to Alzheimer's disease. Experimental approaches to study Aß 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 Aß. We address the differences between the two most common Aß alloforms, Aß40 and Aß42, which oligomerize differently in vitro. Our previous study showed that, despite simplifications, our discrete molecular dynamics approach accounts for the experimentally observed differences between Aß40 and Aß42 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 Aß40 and Aß42 oligomer formation. Our results indicate that EIs promote formation of larger oligomers in both Aß40 and Aß42. Both Aß40 and Aß42 display a peak at trimers/tetramers, but Aß42 displays additional peaks at nonamers and tetradecamers. EIs thus shift the oligomer size distributions to larger oligomers. Nonetheless, the Aß40 size distribution remains unimodal, whereas the Aß42 distribution is trimodal, as observed experimentally. We show that structural differences between Aß40 and Aß42 that already appear in the monomer folding, are not affected by EIs. Aß42 folded structure is characterized by a turn in the C-terminus that is not present in Aß40. We show that the same C-terminal region is also responsible for the strongest intermolecular contacts in Aß42 pentamers and larger oligomers. Our results suggest that this C-terminal region plays a key role in the formation of Aß42 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 Aß42 oligomers may be able to prevent oligomer formation or structurally modify the assemblies to reduce their toxicity.

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