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

Center for Polymer Studies, Department of Physics, Boston University, Boston, Massachusetts, USA.
Biophysical Journal (Impact Factor: 3.97). 07/2007; 92(11):4064-77. DOI: 10.1529/biophysj.106.097766
Source: PubMed


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.

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    • "Furthermore, Yun et al. (2007) showed that electrostatic interactions facilitate oligomerization of both Aβ 40 and Aβ 42 into trimers and tetramers, while Aβ 42 can also form nonamers and tetradecamers due to its extended C-terminus via a quasi-stable turn. The crystal structure of an Aβ 18−41 tetramer (Streltsov et al., 2011) supported the oligomeric structures suggested in these DMD studies. "
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    Journal of Molecular Cell Biology 03/2014; 6(2). DOI:10.1093/jmcb/mju007 · 6.77 Impact Factor
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    • "Amidation of the C-terminus leads to higher order aggregation, supporting this fact. [4] Other studies have noted the difficulty of accommodating a negatively charged terminus in a manner consistent with extensive hydrophobic packing [29]. Since oxidation of M35 blocks aggregation, it is likely that this residue is also buried [30]. "
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    PLoS ONE 11/2012; 7(11):e49375. DOI:10.1371/journal.pone.0049375 · 3.23 Impact Factor
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    • "Substantial successes have been achieved using DMD to predict protein folding [7], analyze protein flexibility [8], macromolecular aggregation [9] [10] [11] [12] [13] [14] [15] [16], macro and supramolecular transitions [17], and protein oligomerization [18] [19]. Recently, DMD with a four-bead peptide model used to study aggregation of amyloid-␤ peptides [18] [19] [20]. This four-bead peptide model has the advantage of specifying left or right handedness of residues with minimal number of beads. "
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