Role of electrostatic interactions in amyloid beta-protein (A beta) oligomer formation: a discrete molecular dynamics study.

Center for Polymer Studies, Department of Physics, Boston University, Boston, Massachusetts, USA.
Biophysical Journal (Impact Factor: 3.83). 07/2007; 92(11):4064-77. DOI: 10.1529/biophysj.106.097766
Source: PubMed

ABSTRACT Pathological folding and oligomer formation of the amyloid beta-protein (A beta) are widely perceived as central to Alzheimer's disease. Experimental approaches to study A beta 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 A beta. We address the differences between the two most common A beta alloforms, A beta 40 and A beta 42, which oligomerize differently in vitro. Our previous study showed that, despite simplifications, our discrete molecular dynamics approach accounts for the experimentally observed differences between A beta 40 and A beta 42 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 A beta 40 and A beta 42 oligomer formation. Our results indicate that EIs promote formation of larger oligomers in both A beta 40 and A beta 42. Both A beta 40 and A beta 42 display a peak at trimers/tetramers, but A beta 42 displays additional peaks at nonamers and tetradecamers. EIs thus shift the oligomer size distributions to larger oligomers. Nonetheless, the A beta 40 size distribution remains unimodal, whereas the A beta 42 distribution is trimodal, as observed experimentally. We show that structural differences between A beta 40 and A beta 42 that already appear in the monomer folding, are not affected by EIs. A beta 42 folded structure is characterized by a turn in the C-terminus that is not present in A beta 40. We show that the same C-terminal region is also responsible for the strongest intermolecular contacts in A beta 42 pentamers and larger oligomers. Our results suggest that this C-terminal region plays a key role in the formation of A beta 42 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 A beta 42 oligomers may be able to prevent oligomer formation or structurally modify the assemblies to reduce their toxicity.


Available from: Brigita Urbanc, Apr 17, 2015
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