RT Journal Article
SR Electronic
T1 Aβ Fibrils Can Act as Aqueous Pores: a Molecular Dynamics Study
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 418137
DO 10.1101/418137
A1 S. Natesh
A1 J. R. Sachleben
A1 T. R Sosnick
A1 K. F. Freed
A1 S. C. Meredith
A1 E. J. Haddadian
YR 2018
UL http://biorxiv.org/content/early/2018/09/14/418137.abstract
AB Aggregation of Aβ peptides is important in the etiology of Alzheimer’s Disease (AD), an increasingly prevalent neurodegenerative disease. We ran multiple ∼ 300 ns all-atom explicit solvent molecular dynamics (MD) simulations starting from three NMR-based structural models of Aβ(1-40 residues) fibrils having 2-fold (pdb code 2LMN) or 3-fold rotational symmetry (2LMP, and 2M4J). The 2M4J structure is based on an AD brain-seeded fibril whereas 2LMP and 2LMN represent two all-synthetic fibrils. Fibrils are constructed to contain either 6 or an infinite number of layers made using periodic images. The 6 layer fibrils partially unravel over the simulation time, mainly at their ends, while infinitely long fibrils do not. Once formed, the D23-K28 salt bridges are very stable and form within and between chains. Fibrils tend to retain (2LMN and 2LMP) or develop (2M4J) a “stagger” or register shift of β-strands along the fibril axis. The brain-seeded fibril rapidly develops gaps at the sides of the fibril, which allows bidirectional flow of water and ions from the bulk phase in and out the central longitudinal core of the fibril. Similar but less marked changes were also observed for the 2LMP fibrils. The residues defining the gaps largely coincide with those demonstrated to have relatively rapid Hydrogen-Deuterium exchange in solid state NMR studies. These observations suggest that Aβ(1-40 residues) fibrils may act as aqueous pores that might disrupt water and ion fluxes if inserted into a cell membrane.