Modeling amyloid beta-peptide insertion into lipid bilayers.
Inspired by recent suggestions that the Alzheimer's amyloid beta peptide (Abeta) can insert into cell membranes and form harmful ion channels, we model insertion of the 40- and 42-residue forms of the peptide into cell membranes using a Monte Carlo code which is specific at the amino acid level. We examine insertion of the regular Abeta peptide as well as mutants causing familial Alzheimer's disease, and find that all but one of the mutants change the insertion behavior by causing the peptide to spend more simulation steps in only one leaflet of the bilayer. We also find that Abeta42, because of the extra hydrophobic residues relative to Abeta40, is more likely to adopt this conformation than Abeta40 in both wild-type and mutant forms. We argue qualitatively why these effects happen. Here, we present our results and develop the hypothesis that this partial insertion increases the probability of harmful channel formation. This hypothesis can partly explain why these mutations are neurotoxic simply due to peptide insertion behavior. We further apply this model to various artificial Abeta mutants which have been examined experimentally, and offer testable experimental predictions contrasting the roles of aggregation and insertion with regard to toxicity of Abeta mutants. These can be used through further experiments to test our hypothesis.
Mobley
David L
DL
Department of Physics, University of California, Davis, California 95616, USA. mobley@physics.ucdavis.edu
Cox
Daniel L
DL
Singh
Rajiv R P
RR
Maddox
Michael W
MW
Longo
Marjorie L
ML
D000465:Algorithms; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels / Q000737:chemistry*; D008051:Lipid Bilayers / Q000378:metabolism*; D008962:Models, Theoretical; D009010:Monte Carlo Method; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D007473:Ion Channels; D008051:Lipid Bilayers; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)