  Inspired by recent suggestions that the Alzheimer's amyloid beta peptide (A
beta) 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 A-beta 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 A-beta 42, because of the
extra hydrophobic residues relative to A-beta 40, is more likely to adopt this
conformation than A-beta 40 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 A-beta mutants which have been examined
experimentally, and offer testable experimental predictions contrasting the
roles of aggregation and insertion with regard to toxicity of A-beta mutants.
These can be used through further experiments to test our hypothesis.
