Does the inclusion of electronic polarisability lead to a better modelling of peptide aggregation?

Abstract

Simulating the process of amyloid aggregation with atomic detail is a challenging task for various reasons. One of them is that it is difficult to parametrise a force field such that all protein states ranging from the folded through the unfolded to the aggregated state are represented with the same level of accuracy. Here, we test whether the consideration of electronic polarisability improves the description of the different states of Aβ_16-22. Surprisingly, the CHARMM Drude polarisable force field is found to perform worse than its unpolarisable counterpart CHARMM36m. Sources for this failure of the Drude model are discussed.

Fig. 1. Results for the Aβ_16–22 monomer. (A) Number of Na⁺ (left) and Cl⁻ (right) within 0.5 nm of the CA atom per peptide residue. (B) Radial distribution ρ(r) of Na⁺ around the carbonyl-oxygen atom of K16 (left) and E22 (right). The insets show the zoomed-in results for C36m. (C) Secondary structure propensity of the peptide based on ϕ and ψ. (D) The average number of H-bonds formed between the peptide residues and water. The dashed regions indicate the share of the Aβ_16–22 residues being the hydrogen donors, otherwise they are the hydrogen acceptors. In all panels the results obtained with C-Drude and C36m are shown in blue and orange, respectively. In (C) and (D) the results that were obtained with C-Drude with no salt (NS) are shown too (green). All results are averages over the three MD runs per system and the error bars indicate the standard errors of the mean.

Fig. 2. Transition networks of Aβ_16–22 dimerisation obtained with (A) C-Drude and (B) C36m. The states are defined by the oligomer size (1 or 2), the nematic order parameter (−1, 0, or 1) and the peptide-averaged amount of residues in β-strand conformation (from 0 to 7). The size of the nodes reflects the population of the corresponding state and the thickness of the lines corresponds to the transition probability. Only nodes with at least 1% of the total population are shown. Representative structures for some of the nodes are presented as cartoons, where the β-sheets are coloured in yellow and the side chains of the terminal residues K16 (blue) and E22 (red) are shown explicitly.