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Modeling Amyloid ß-Peptide Insertion into Lipid Bilayers

David L. Mobley ^*, Daniel L. Cox ^*, Rajiv R. P. Singh ^*, Michael W. Maddox  and Marjorie L. Longo 

^* Department of Physics, and Department of Chemical Engineering and Materials Science, University of California, Davis, California

Correspondence: Address reprint requests to David Lowell Mobley, Physics Department, University of California at Davis, One Shields Avenue, Davis, CA 95616. Tel.: 530-752-0446; E-mail: mobley{at}physics.ucdavis.edu; web: http://asaph.ucdavis.edu/dmobley.

Inspired by recent suggestions that the Alzheimer's amyloid ß peptide (Aß) 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 Aß 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 Aß42, because of the extra hydrophobic residues relative to Aß40, is more likely to adopt this conformation than Aß40 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 Aß mutants which have been examined experimentally, and offer testable experimental predictions contrasting the roles of aggregation and insertion with regard to toxicity of Aß mutants. These can be used through further experiments to test our hypothesis.

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