Paper Citing NAMD - Abstract
Jang, Hyunbum; Arce, Fernando Teran; Ramachandran, Srinivasan; Kagan, Bruce L.; Lal, Ratnesh; Nussinov, Ruth
Familial Alzheimer's Disease Osaka Mutant (Delta E22) beta-Barrels Suggest an Explanation for the Different A beta(1-40/42) Preferred Conformational States Observed by Experiment
JOURNAL OF PHYSICAL CHEMISTRY B, 117:11518-11529, OCT 3 2013
An unusual Delta E693 mutation in the amyloid precursor protein (APP) producing a beta-amyloid (A beta) peptide lacking glutamic acid at position 22 (Glu22) was recently discovered, and dabbed the Osaka mutant (Delta E22). Previously, several point mutations in the A beta peptide involving Glu22 substitutions were identified and implicated in the early onset of familial Alzheimer's disease (FAD). Despite the absence of Glu22, the Osaka mutant is also associated with FAD, showing a recessive inheritance in families affected by the disease. To see whether this aggregation-prone A beta mutant could directly relate to the A beta ion channel-mediated mechanism as observed for the wild type (WT) Ail peptide in A beta pathology, we modeled Osaka mutant beta-barrels in a lipid bilayer. Using molecular dynamics (MD) simulations, two conformer Delta E22 barrels with the U-shaped monomer conformation derived from NMR-based WT A beta fibrils were simulated in explicit lipid environment. Here, we show that the Delta E22 barrels obtain the lipid-relaxed beta-sheet channel topology, indistinguishable from the WT A beta(1-42) barrels, as do the outer and pore dimensions of octadecameric (18-mer) Delta E22 barrels. Although the Delta E22 barrels lose the cationic binding site in the pore which is normally provided by the negatively charged Glu22 side chains, the mutant pores gain a new cationic binding site by Glu11 at the lower bilayer leaflet, and exhibit ion fluctuations similar to the WT barrels. Of particular interest, this deletion mutant suggests that toxic WT A beta(1-42) would preferentially adopt a less C-terminal turn similar to that observed for A beta(17-42), and explains why the solid state NMR data for A beta(1-40) point to a more C-terminal turn conformation. The observed Delta E22 barrels conformational preferences also suggest an explanation for the lower neurotoxicity in rat primary neurons as compared to WT A beta(1-42).
