In Silico Study of Full-Length Amyloid β 1−42 Tri- and Penta-Oligomers in Solution

Abstract

Amyloid oligomers are considered to play causal roles in the pathogenesis of amyloid-related degenerative diseases including Alzheimer's disease. Using MD simulation techniques, we explored the contributions of the different structural elements of trimeric and pentameric full-length Abeta1-42 aggregates in solution to their stability and conformational dynamics. We found that our models are stable at a temperature of 310 K, and converge toward an interdigitated side-chain packing for intermolecular contacts within the two beta-sheet regions of the aggregates: beta1 (residues 18-26) and beta2 (residues 31-42). MD simulations reveal that the beta-strand twist is a characteristic element of Abeta-aggregates, permitting a compact, interdigitated packing of side chains from neighboring beta-sheets. The beta2 portion formed a tightly organized beta-helix, whereas the beta1 portion did not show such a firm structural organization, although it maintained its beta-sheet conformation. Our simulations indicate that the hydrophobic core comprising the beta2 portion of the aggregate is a crucial stabilizing element in the Abeta aggregation process. On the basis of these structure-stability findings, the beta2 portion emerges as an optimal target for further antiamyloid drug design.

Replica exchange molecular dynamics of the thermodynamics of fibril growth of Alzheimer's Aβ42 peptide

“…Finally, in a third step, the loop from 27ASN to 30ALA, connecting C-terminal and N-terminal strand, with its hydrophilic residues assumes the form observed in fibrils. The role of C-terminal β-sheet formation as driving force for fibril elongation is also supported by work of Masman et al 29 who studied the same molecule but with different force field. On the other hand, Takeda and Klimov 19 found that the N-terminal strand segment of incoming monomer forms parallel hydrogen bond with the corresponding segments of peptides in the fibril.…”

“…As experiments have indicated 20,21 that the Aβ peptide deposits to the fibril predominantly as a monomer, we simulate the interaction between a monomer and a pre-structured fibril, and compare our observed monomer structures with the solid-state NMRstructures of Aβ peptides in a fibril. Unlike Buchete et al 28 and Masman et al 29 we study directly the fibril elongation process, not the time-reversed process of aggregate dissociation. By simulating the full-length Aβ 42 peptide we also go beyond previous work that studied similar questions but relied on short fragments such as Aβ (16)(17)(18)(19)(20)(21)(22), 22,23 Aβ(35-40), 24,26 or Aβ(37-42).…”

In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

“…19 To obtain an Ab dimer (lowest free energy), two of the same monomers were used. The ClusPro2.0 server, one of the top performers at CAPRI (Critical Assessment of Predicted Interactions) round [13][14][15][16][17][18][19]20 was used to predict the possible structure of the oligomers. We submitted to ClusPro two monomers to obtain the dimer, which was used to dock with another monomer to form a trimer, and so forth; this process was performed until an Ab pentamer was formed.…”

Molecular Simulations of Human and Mouse Aβ1–16 at Different pH Values: Structural Characteristics toward Understanding Cu2+‐Coordinated Amyloid Beta Spheres

“…[41] Vand er Waals forces were treated using a1 .0 nm cutoff. At ime step of 0.002 ps, which had been adopted to successfully deal with such systems, [42,43] was used for our simulations. TIP3P [44] water molecules were filled in adodecahedron box.…”

“…Even though in af ibril generated by af ull-length Ab 1-42 ,A b 1-16 is also found to be of disordered structure morphology. [42,49] Thus Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] fragment is difficult to investigate alone. To clarify the inconsistencies and simplifyt he investigation, we adopted an ew center-distance statistical method (CDSM) to analyze the available His coordination sites and their order of priority upon the Cu 2 + binding to mouseo r human Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] .T he reliability of the method is established on ab asis that the metal ion (M) coordination sites of an Ab [1][2][3][4][5][6][7][8][9][10][11][12][13]…”