Effects of All-Atom Molecular Mechanics Force Fields on Amyloid Peptide Assembly: The Case of PHF6 Peptide of Tau Protein.

Molecular dynamics (MD) simulations play a vital role in revealing the mechanism of amyloid aggregation that is crucial to the therapeutic agent development for Alzheimer's Disease. However, the accuracy of MD simulation results strongly depends on the force field employed. In our previous benchmark for 17 all-atom force fields on modeling of amyloid aggregation using the Aβ16-22 dimer, we showed that AMBER14SB and CHARMM36m are suitable force fields for amyloid aggregation simulation, while GROMOS54a7 and OPLSAA are not good for the task. In this work, we continue assessing the applicability of atomistic force fields on amyloid aggregation using the VQIVYK (PHF6) peptide which is essential for tau-protein aggregation. Although, both Aβ16-22 and PHF6 peptides formed fibrils in vitro, the PHF6 fibrils are parallel β-sheets, while the Aβ16-22 fibrils are antiparallel β-sheets. We performed an all-atom large-scale MD simulation in explicit water on the PHF6 dimer and octa-peptides systems using five mainstream force fields, including AMBER99SB-disp, AMBER14SB, CHARMM36m, GROMOS54a7, and OPLSAA. The accumulated simulation time is 0.2 ms. Our result showed that the β-sheet structures of PHF6 peptides sampled by AMBER99SB-disp, AMBER14SB, GROMOS54a7, and OPLSAA are in favor of the antiparallel β-sheets, while the dominant type of β-sheet structures is parallel β-sheet by using CHARMM36m. Among the five force fields, CHARMM36m provides the strongest CH-π interaction that was observed in an NMR study. The comparison between our results and experimental observation indicates that CHARMM36m achieved the best performance on modeling the aggregation of PHF6 peptides. In summary, CHARMM36m is currently the most suitable force field for studying the aggregation of both amyloid-β and Tau through MD simulations.