Probing Energetics of Aβ Fibril Elongation by Molecular Dynamics Simulations

Using replica exchange molecular dynamics simulations and an all-atom implicit solvent model, we probed the energetics of A beta(10-40) fibril growth. The analysis of the interactions between incoming A beta peptides and the fibril led us to two conclusions. First, considerable variations in fibril binding propensities are observed along the A beta sequence. The peptides in the fibril and those binding to its edge interact primarily through their N-termini. Therefore, the mutations affecting the A beta positions 10-23 are expected to have the largest impact on fibril elongation compared with those occurring in the C-terminus and turn. Second, we performed weak perturbations of the binding free energy landscape by scanning partial deletions of side-chain interactions at various A beta sequence positions. The results imply that strong side-chain interactions-in particular, hydrophobic contacts-impede fibril growth by favoring disordered docking of incoming peptides. Therefore, fibril elongation may be promoted by moderate reduction of A beta hydrophobicity. The comparison with available experimental data is presented.