Molecular dynamics simulation of amyloid β dimer formation

Recent experiments with amyloid β (Aβ) peptide indicate that formation of toxic oligomers may be an important contribution to the onset of Alzheimer's disease. The toxicity of Aβ oligomers depends on their structure, which is governed by assembly dynamics. Due to limitations of current experimental techniques, a detailed knowledge of oligomer structure at the atomic level is missing. We introduce a molecular dynamics approach to study Aβ dimer formation. 1), We use discrete molecular dynamics simulations of a coarse-grained model to identify a variety of dimer conformations; and 2), we employ all-atom molecular mechanics simulations to estimate thermodynamic stability of all dimer conformations. Our simulations of a coarse-grained Aβ peptide model predicts 10 different planar β-strand dimer conformations. We then estimate the free energies of all dimer conformations in all-atom molecular mechanics simulations with explicit water. We compare the free energies of Aβ(1-42) and Aβ(1-40) dimers. We find that 1), dimer conformations have higher free energies compared to their corresponding monomeric states; and 2), the free-energy difference between the Aβ(1-42) and the corresponding Aβ(1-40) dimer conformation is not significant. Our results suggest that Aβ oligomerization is not accompanied by the formation of thermodynamically stable planar β-strand dimers.