Molecular dynamics simulations of spontaneous fibril formation by random-coil peptides

Abstract

Assembly of normally soluble proteins into amyloid fibrils is a cause or associated symptom of numerous human disorders, including Alzheimer's and the prion diseases. We report molecular-level simulation of spontaneous fibril formation. Systems containing 12-96 model polyalanine peptides form fibrils at temperatures greater than a critical temperature that decreases with peptide concentration and exceeds the peptide's folding temperature, consistent with experimental findings. Formation of small amorphous aggregates precedes ordered nucleus formation and subsequent rapid fibril growth through addition of beta-sheets laterally and monomeric peptides at fibril ends. The fibril's structure is similar to that observed experimentally.

Fig. 1.

Geometry of the intermediate-resolution protein model, PRIME, for polyalanine. Covalent bonds are shown with gray lines connecting united atoms. At least one of each type of pseudobond is shown with a color line. Pseudobonds are used to maintain backbone bond angles, consecutive C_a distances, and residue l-isomerization. The united atoms are not shown full size for ease of viewing.

Fig. 2.

Snapshots of the 48-peptide system at various reduced times, t^*, during a simulation (see Movie 1, which is published as supporting information on the PNAS web site) at c = 10 mM and T^* = 0.14 that results in a fibril. Hydrophobic sidechains are red; colors of backbone atoms on different peptides are assigned to make it easy to distinguish the various sheets in the resulting fibril. United atoms are not shown full size for ease of viewing.

Fig. 3.

The percentage of peptides in fibril structures versus reduced time, t^*, in the seeded and unseeded simulations at c = 2.0 mM and T^* = 0.14.

Fig. 4.

The percentage of peptides in α-helices (a) and fibrils (b) versus the reduced temperature T^* at different peptide concentrations: 0.5 mM (black circles), 1.0 mM (red circles), 2.5 mM (green diamonds), 5 mM (blue triangles), 10 mM (purple triangles), and 20 mM (orange triangles).

Fig. 5.

A close-up snapshot of the 96-peptide fibrillar structure formed at c = 5.0 mM and T^* = 0.13 viewed down the fibril (z) axis.