Putative Pore Structures of Amyloid β 25–35 in Lipid Bilayers

Abstract

The amyloid β peptide aggregates to form extracellular plaques in the brains of Alzheimer's disease patients. Certain of its fragments have been found to have similar properties to those of the full-length peptide. The best-studied of these is 25-35, which aggregates into fibrils, is toxic to neurons, and forms ion channels in synthetic lipid bilayers. Here, we investigate possible pore-forming structures of oligomers of this peptide in a POPC/ POPG membrane. We consider octameric and decameric β-barrels of different topology, strand orientation, and shear, evaluate their stability in an implicit membrane model, and subject the best models to multimicrosecond all-atom molecular dynamics simulations. We find two decameric structures that are kinetically stable in membranes on this time scale: an imperfectly closed antiparallel β-barrel with K28 in the pore lumen and a short parallel β-barrel with K28 toward the membrane interface. Both structures exhibit dehydrated gaps in the pore lumen, which are larger for the antiparallel barrel. Based on these results, the experimental cation selectivity, the dependence of ion channel activity on voltage direction, and certain mutation data, the parallel model seems more compatible with experimental data.

Transmembrane β-Barrel Models of α-Synuclein Oligomers

“…The picture obtained by these studies is likely to be dominated by the extramembranous portions of the protein. We recently applied our methodology to IAPP, amyloid β 1–42, and amyloid β 25–35 and found reasonably stable β-barrel structures in each case. A recent computational study of a generic FKFE repeat sequence found spontaneous formation of imperfect beta barrels on the time scale of a few μs at somewhat elevated temperatures .…”

Knockout Mouse Studies Show Mitochondrial CLPP Peptidase and CLPX Unfoldase to Act in Matrix Condensates Near IMM, as Fast Stress Response in Protein Assemblies for Transcript Processing, Translation, and Heme Production

“…Thus, these condensates may be defined by the multivalent interaction forces that keep long and flexible molecules such as lipids or RNA together [203,204]. They are also defined by the vulnerable reaction intermediates that need protection from the aqueous or membrane phases, such as cleaved unfolded RNA without modifications, or unchelated porphyrins that are unassembled with proteins, or pre-fibril oligomers with a propensity to disrupt membranes [205][206][207]. Regarding its multivalent interaction forces and its long flexible structure, RNA was the prime example to understand LLPS, based on the phase contrast during microscopic visualization of the nucleolus.…”

Knockout Mouse Studies Show That Mitochondrial CLPP Peptidase and CLPX Unfoldase Act in Matrix Condensates near IMM, as Fast Stress Response in Protein Assemblies for Transcript Processing, Translation, and Heme Production

“…Thus, these condensates may be defined by the multivalent interaction forces that keep long and flexible molecules such as lipids or RNA together [ 203 , 204 ]. They are also defined by the vulnerable reaction intermediates that need protection from the aqueous or membrane phases, such as cleaved unfolded RNA without modifications, unchelated porphyrins that are unassembled with proteins, or pre-fibril oligomers with a propensity to disrupt membranes [ 205 , 206 , 207 ]. Regarding its multivalent interaction forces and its long flexible structure, RNA was the prime example for understanding LLPS, based on the phase contrast during the microscopic visualization of the nucleolus.…”