Temperature-induced dissociation of Abeta monomers from amyloid fibril.
Using all-atom molecular dynamics, we study the temperature-induced dissociation of Abeta monomers from the fibril protofilament. To accelerate conformational sampling, simulations are performed at elevated temperatures and peptide concentrations. By computing free energy disconnectivity graphs we mapped the free energy landscape of monomers on the surface of Abeta fibril. We found that Abeta monomers sample diverse sets of low free energy states with different degrees of association with the fibril. Some of these states have residual amounts of fibril interactions, whereas others lack fibril-like content. Generally, Abeta monomers with partially formed fibril-like interactions have the lowest free energies, but their backbone conformations may differ considerably from those in the fibril interior. Overall, Abeta amyloid protofilaments seem to be highly resistant to thermal dissociation. Monomer dissociation from the fibril edge proceeds via multiple stages and pathways. Our simulation findings are discussed in the context of recent experimental results.
Takeda
Takako
T
Department of Bioinformatics and Computational Biology, George Mason University, Manassas, Virginia 20110, USA.
Klimov
Dmitri K
DK
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure*; D003198:Computer Simulation; D008956:Models, Chemical; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D011489:Protein Denaturation; D013696:Temperature
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments