Paper Citing NAMD - Abstract
Yu, Xiang; Zheng, Jie
Polymorphic Structures of Alzheimer's beta-Amyloid Globulomers
PLOS ONE, 6 Art. No. e20575, JUN 7 2011
Background: Misfolding and self-assembly of Amyloid-beta (A beta) peptides into amyloid fibrils is pathologically linked to the development of Alzheimer's disease. Polymorphic A beta structures derived from monomers to intermediate oligomers, protofilaments, and mature fibrils have been often observed in solution. Some aggregates are on-pathway species to amyloid fibrils, while the others are off-pathway species that do not evolve into amyloid fibrils. Both on-pathway and off-pathway species could be biologically relevant species. But, the lack of atomic-level structural information for these A beta species leads to the difficulty in the understanding of their biological roles in amyloid toxicity and amyloid formation. Methods and Findings: Here, we model a series of molecular structures of A beta globulomers assembled by monomer and dimer building blocks using our peptide-packing program and explicit-solvent molecular dynamics (MD) simulations. Structural and energetic analysis shows that although A beta globulomers could adopt different energetically favorable but structurally heterogeneous conformations in a rugged energy landscape, they are still preferentially organized by dynamic dimeric subunits with a hydrophobic core formed by the C-terminal residues independence of initial peptide packing and organization. Such structural organizations offer high structural stability by maximizing peptide-peptide association and optimizing peptide-water solvation. Moreover, curved surface, compact size, and less populated beta-structure in A beta globulomers make them difficult to convert into other high-order A beta aggregates and fibrils with dominant beta-structure, suggesting that they are likely to be off-pathway species to amyloid fibrils. These A beta globulomers are compatible with experimental data in overall size, subunit organization, and molecular weight from AFM images and H/D amide exchange NMR. Conclusions: Our computationally modeled A beta globulomers provide useful insights into structure, dynamics, and polymorphic nature of A beta globulomers which are completely different from A beta fibrils, suggesting that these globulomers are likely off-pathway species and explaining the independence of the aggregation kinetics between A beta globulomers and fibrils.
