A condensation-ordering mechanism in nanoparticle-catalyzed peptide aggregation

Abstract

Nanoparticles introduced in living cells are capable of strongly promoting the aggregation of peptides and proteins. We use here molecular dynamics simulations to characterise in detail the process by which nanoparticle surfaces catalyse the self-assembly of peptides into fibrillar structures. The simulation of a system of hundreds of peptides over the millisecond timescale enables us to show that the mechanism of aggregation involves a first phase in which small structurally disordered oligomers assemble onto the nanoparticle and a second phase in which they evolve into highly ordered as their size increases.

Figure 1. Illustration of the “condensation-ordering” mechanism of peptide self-assembly in the presence of a hydrophobic nanoparticle.

(A) Initially, at microseconds, the peptides are in their monomeric state. (B) At intermediate times, milliseconds, small oligomeric assemblies form on the nanoparticle surface. (C) At later times, milliseconds, these oligomers re-order into fibrillar structures as their size increases. Peptides that do not form intermolecular hydrogen bonds are shown in blue, while peptides that form intermolecular hydrogen bonds are assigned a random colour, which is the same for peptides that belong to the same . Two peptides are defined as belonging to the same cluster if their centres of mass distance is less than 5 Å. Two peptides are taken to participate within a if they form more than four inter-chain hydrogen bonds with each other. The spherical nanoparticle is displayed in orange in the centre of the simulation box; the diameter of the peptides is slightly reduced for illustration purposes. Panels (B) and (C) show enlarged views of the nanoparticle-peptide system. The simulation was performed at , , , and .

Figure 2. Structural analysis of the nanoparticle-induced self-assembly mechanism.

(A) Average size of the largest cluster observed during a simulation in presence of a hard sphere nanoparticle: , (green line), and several hydrophobic nanoparticles that differ in diameter and hydrophobicity: , (blue line), , (red line), and , (black line). The results are averaged over ten independent simulation runs and the error bars correspond to the standard deviation of the mean. (B) Number of clusters of size as a function of time: microseconds (left), milliseconds (middle), milliseconds (right), for the MD trajectory and parameters described in Fig. 1. Black lines correspond to all clusters formed in the system; red lines correspond to the number of clusters formed on the nanoparticle surface. (C) Structural order parameter as a function of the cluster size averaged over ten independent simulations. The line colours are as described in (A). (D) Normalized density profile , where is the bulk density of the system, as a function of the distance from the centre of mass of the nanoparticle at the beginning of the simulation, microseconds (left panel), intermediate times, milliseconds (middle panel), and at the end milliseconds (right panel). The different line colours are as described in (A) and correspond to the different seed sizes and peptide seed interaction energies. The results are averaged over ten independent simulations and the error bars correspond to the standard deviation of the mean.

Figure 3. Illustration of the condensation-ordering mechanism for different hydrophobicity of the nanoparticle, nanoparticle diameter.

(A) , at microseconds(left), milliseconds (middle), milliseconds (right). (B) , at microseconds (left), milliseconds (middle), milliseconds (right). The concentration and temperature are , respectively, and the colour code is as described in Fig 1.

Figure 4. Normalised histograms of distances between atoms involved in backbone-backbone hydrogen bonds.

The analysis is based on 500 high resolution PDB structures and used to define hydrogen bonds in the protein model employed in our simulation. (A) Histogram of distances and between atoms and used to define a helical hydrogen bond assigned to atoms with . (B) Histogram of distances between atoms that form a parallel, anti-parallel, or helical hydrogen bond. For the helical hydrogen bond . (C) Illustration of the alternation of distances for consecutive atoms that form anti-parallel hydrogen bonds. (D) as in (C). (E) The distance is used to define hydrogen bonds between atoms in parallel and anti parallel . (F) Distances used to define cooperative hydrogen bonds between two consecutive atoms and that form parallel or and that form anti parallel .