Beta2-microglobulin amyloid fragment organization and morphology and its comparison to Abeta suggests that amyloid aggregation pathways are sequence specific.

Beta2-microglobulin (beta2-m) can form dialysis-related amyloid deposits. The structure of a fragment of beta2-m (K3, Ser20-Lys41) in the oligomeric state has recently been solved. We modeled equilibrium structures of K3 oligomers with different organizations (single and double layers) and morphologies (linear-like and annular-like) for the wild-type and mutants using all-atom molecular dynamics (MD) simulations. We focused on the sheet-to-sheet association force, which is the key in the amyloid organization and morphology. For the linear-like morphology, we observed two stable organizations: (i) single-layered parallel-stranded beta-sheets and (ii) double-layered parallel-stranded antiparallel beta-sheets stacked perpendicular to the fibril axis through the hydrophobic N-terminal-N-terminal (NN) interface. No stable annular structures were observed. The structural instability of the annular morphology was mainly attributed to electrostatic repulsion of three negatively charged residues (Asp15, Glu17, and Asp19) projecting from the same beta-strand surface. Linear-like and annular-like double-layered oligomers with the NN interface are energetically more favorable than other oligomers with C-terminal-C-terminal (CC) or C-terminal-N-terminal (CN) interfaces, emphasizing the importance of hydrophobic interactions and side-chain packing in stabilizing these oligomers. Moreover, only linear-like structures, rather than annular structures, with parallel beta-strands and antiparallel beta-sheet arrangements are possible intermediate states for the K3 beta2-m amyloid fibrils in solution. Comparing the beta2-m fragment with Abeta indicates that while both adopt similar beta-strand-turn-beta-strand motifs, the final amyloid structures can be dramatically different in size, structure, and morphology due to differences in side-chain packing arrangements, intermolecular driving forces, sequence composition, and residue positions, suggesting that the mechanism leading to distinct morphologies and the aggregation pathways is sequence specific.