Article

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

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.

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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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    ABSTRACT: The brevity of molecular dynamics simulations often limits their utility in developing and evaluating structural models of proteins. The duration of simulations can be increased greatly using discrete molecular dynamics (DMD). However, the trade off is that coarse graining, implicit solvent, and other time-saving procedures reduce the accuracy of DMD simulations. Here we address some of these issues by comparing results of DMD and conventional all atom MD simulations on proteins of known structure and misfolded proteins. DMD simulations were performed at a range of temperatures to identify a 'physiological' temperature for DMD that mimicked molecular motions of conventional MD simulations at 310K. We also compared results obtained with a new implicit solvent model developed here based on Miyazawa-Jernigan interaction pair potential to those obtained with a previously used model based on Kyte-Doolittle hydropathy scale. We compared DMD and all atom molecular dynamics with explicit water by simulating both correctly and incorrectly folded structures, and monomeric and dimeric α β-barrel structures to analyze the ability of these procedures to distinguish between good and bad models. Deviations from the correct structures were substantially greater with DMD, as would be expected from coarse-graining and longer simulation time. Deviations were smallest for β-strands and greatest for coiled loops. Structures of the incorrectly folded models were very poorly preserved during the DMD simulations; but both methods were able to distinguish between the correct and the incorrect structures based on differences in the magnitudes of the root mean squared deviation (RMSD) from the starting conformation.
    Journal of molecular graphics & modelling 02/2011; 29(5):663-75. DOI:10.1016/j.jmgm.2010.12.002 · 2.02 Impact Factor
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    • "Indeed, there are many examples of ''off-pathway'' stable and metastable oligomeric and fibrillar amyloid species (Gellermann et al., 2008; Necula et al., 2007; Ehrnhoefer et al., 2008; Gosal et al., 2005). The dynamic and heterogeneous nature of the aggregates makes kinetic studies challenging (Yun et al., 2007; Bitan et al., 2005). At the same time, given the proposed role of oligomers in affecting cytotoxicity in diverse diseases, further understanding of their placement within or separate from mature amyloid fibril assembly pathways is needed. "
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    Journal of Structural Biology 01/2011; 173(1):1-13. DOI:10.1016/j.jsb.2010.09.018 · 3.23 Impact Factor
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    • "Indeed, there are many examples of ''off-pathway'' stable and metastable oligomeric and fibrillar amyloid species (Gellermann et al., 2008; Necula et al., 2007; Ehrnhoefer et al., 2008; Gosal et al., 2005). The dynamic and heterogeneous nature of the aggregates makes kinetic studies challenging (Yun et al., 2007; Bitan et al., 2005). At the same time, given the proposed role of oligomers in affecting cytotoxicity in diverse diseases, further understanding of their placement within or separate from mature amyloid fibril assembly pathways is needed. "
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    ABSTRACT: Amyloid fibrils are filamentous protein aggregates implicated in several common diseases such as Alzheimer’s disease and type II diabetes. Similar structures are also the molecular principle of the infectious spongiform encephalopathies such as Creutzfeldt–Jakob disease in humans, scrapie in sheep, and of the so-called yeast prions, inherited non-chromosomal elements found in yeast and fungi. Scanning transmission electron microscopy (STEM) is often used to delineate the assembly mechanism and structural properties of amyloid aggregates. In this review we consider specifically contributions and limitations of STEM for the investigation of amyloid assembly pathways, fibril polymorphisms and structural models of amyloid fibrils. This type of microscopy provides the only method to directly measure the mass-per-length (MPL) of individual filaments. Made on both in vitro assembled and ex vivo samples, STEM mass measurements have illuminated the hierarchical relationships between amyloid fibrils and revealed that polymorphic fibrils and various globular oligomers can assemble simultaneously from a single polypeptide. The MPLs also impose strong constraints on possible packing schemes, assisting in molecular model building when combined with high-resolution methods like solid-state nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR).
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