dorsal/arxiv
View SchemaModeling Amyloid Beta Peptide Insertion into Lipid Bilayers
| Authors | David L. Mobley, Daniel L. Cox, Rajiv R. P. Singh, Michael W. Maddox, Marjorie L. Longo |
|---|---|
| Categories | |
| ArXiv ID | physics/0307143 |
| URL | https://arxiv.org/abs/physics/0307143 |
| DOI | 10.1529/biophysj.103.032342 |
Abstract
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.
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"abstract": "Inspired by recent suggestions that the Alzheimer\u0027s amyloid beta peptide (A\nbeta) can insert into cell membranes and form harmful ion channels, we model\ninsertion of the 40 and 42 residue forms of the peptide into cell membranes\nusing a Monte Carlo code which is specific at the amino acid level. We examine\ninsertion of the regular A-beta peptide as well as mutants causing familial\nAlzheimer\u0027s disease, and find that all but one of the mutants change the\ninsertion behavior by causing the peptide to spend more simulation steps in\nonly one leaflet of the bilayer. We also find that A-beta 42, because of the\nextra hydrophobic residues relative to A-beta 40, is more likely to adopt this\nconformation than A-beta 40 in both wild-type and mutant forms. We argue\nqualitatively why these effects happen. Here, we present our results and\ndevelop the hypothesis that this partial insertion increases the probability of\nharmful channel formation. This hypothesis can partly explain why these\nmutations are neurotoxic simply due to peptide insertion behavior. We further\napply this model to various artificial A-beta mutants which have been examined\nexperimentally, and offer testable experimental predictions contrasting the\nroles of aggregation and insertion with regard to toxicity of A-beta mutants.\nThese can be used through further experiments to test our hypothesis.",
"arxiv_id": "physics/0307143",
"authors": [
"David L. Mobley",
"Daniel L. Cox",
"Rajiv R. P. Singh",
"Michael W. Maddox",
"Marjorie L. Longo"
],
"categories": [
"physics.bio-ph",
"physics.comp-ph",
"physics.med-ph",
"q-bio.BM"
],
"doi": "10.1529/biophysj.103.032342",
"title": "Modeling Amyloid Beta Peptide Insertion into Lipid Bilayers",
"url": "https://arxiv.org/abs/physics/0307143"
},
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