2003/07/31 by David L. Mobley, D. L. Cox, Daniel L. Cox +4
Biochemistry, Genetics and Molecular Biology · Chemistry · Computer Science · Materials Science · Medicine · Physics and Astronomy · #Alzheimer's disease research and treatments #Amyloid (mycology) #Bilayer #Biochemistry #Biology #Biophysics #Chemistry #Computational Drug Discovery Methods #Gene #Lipid bilayer #Membrane #Mutant #Peptide #Supramolecular Self-Assembly in Materials #Wild type #physics.bio-ph #physics.comp-ph #physics.med-ph #q-bio.BM
paper · pdf · doi:10.1529/biophysj.103.032342
14 pages; 8 figures; 2nd revision
arxiv created 2004/01/24 · openalex publication_date 2004/06/01 · arxiv updated 2009/12/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/06
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.