Mechanism of fiber assembly: treatment of Aβ peptide aggregation with a coarse-grained united-residue force field.
The growth mechanism of β-amyloid (Aβ) peptide fibrils was studied by a physics-based coarse-grained united-residue model and molecular dynamics (MD) simulations. To identify the mechanism of monomer addition to an Aβ(1-40) fibril, we placed an unstructured monomer at a distance of 20 Å from a fibril template and allowed it to interact freely with the latter. The monomer was not biased towards fibril conformation by either the force field or the MD algorithm. With the use of a coarse-grained model with replica-exchange molecular dynamics, a longer timescale was accessible, making it possible to observe how the monomers probe different binding modes during their search for the fibril conformation. Although different assembly pathways were seen, they all follow a dock-lock mechanism with two distinct locking stages, consistent with experimental data on fibril elongation. Whereas these experiments have not been able to characterize the conformations populating the different stages, we have been able to describe these different stages explicitly by following free monomers as they dock onto a fibril template and to adopt the fibril conformation (i.e., we describe fibril elongation step by step at the molecular level). During the first stage of the assembly ("docking"), the monomer tries different conformations. After docking, the monomer is locked into the fibril through two different locking stages. In the first stage, the monomer forms hydrogen bonds with the fibril template along one of the strands in a two-stranded β-hairpin; in the second stage, hydrogen bonds are formed along the second strand, locking the monomer into the fibril structure. The data reveal a free-energy barrier separating the two locking stages. The importance of hydrophobic interactions and hydrogen bonds in the stability of the Aβ fibril structure was examined by carrying out additional canonical MD simulations of oligomers with different numbers of chains (4-16 chains), with the fibril structure as the initial conformation. The data confirm that the structures are stabilized largely by hydrophobic interactions and show that intermolecular hydrogen bonds are highly stable and contribute to the stability of the oligomers as well.
Rojas
Ana
A
Department of Physics and Astronomy, Louisiana State University, Baton Rouge, LA 70803, USA.
Liwo
Adam
A
Browne
Dana
D
Scheraga
Harold A
HA
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001665:Binding Sites; D055592:Biophysical Phenomena; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D046912:Multiprotein Complexes / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry*; D055503:Protein Multimerization; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary
D016229:Amyloid beta-Peptides; D046912:Multiprotein Complexes; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)