Effects of all-atom force fields on amyloid oligomerization: replica exchange molecular dynamics simulations of the Aβ16–22 dimer and trimer

Abstract

The aim of this work is to investigate the effects of molecular mechanics force fields on amyloid peptide assembly. To this end, we performed extensive replica exchange molecular dynamics (REMD) simulations on the monomer, dimer and trimer of the seven-residue fragment of the Alzheimer's amyloid-β peptide, Aβ(16-22), using the AMBER99, GROMOS96 and OPLS force fields. We compared the force fields by analysing the resulting global and local structures as well as the free energy landscapes at 300 K. We show that AMBER99 strongly favors helical structures for the monomer and does not predict any β-sheet structure for the dimer and trimer. In contrast, the dimer and trimer modeled by GROMOS96 form antiparallel β-sheet structures, while OPLS predicts diverse structures. Overall, the free energy landscapes obtained by three force fields are very different, and we also note a weak structural dependence of our results on temperature. The implications of this computational study on amyloid oligomerization, fibril growth and inhibition are also discussed.

Effects of Zn2+ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp1 or Glu11?

“…30 between Asp 23 and Lys 28 . 23 In contrast, according to the solidstate NMR studies of Zn 2+ binding to Aβ42 fibrils carried out at room temperature and pH 7.4, major structural changes happened in the N-terminus and the loop region (residues 23−31).…”

Side‐chain hydrophobicity and the stability of Aβ16–22 aggregates

“…Nguyen et al 29 recently compared the differences in structures and energetic of the monomer, dimer, and trimers of Ab [16][17][18][19][20][21][22] resulting from various all-atom force fields. However, although previous explicit solvent all-atom molecular dynamics studies of preformed aggregates used a large range of force fields, to our best knowledge, there are no numerical studies that have investigated the effect of the various force fields on the stability of amyloid aggregates.…”

Stability of Amyloid Oligomers

“…For instance, Xiao, Zhu, Ji, and Zhang (2013) discuss the impact of an electrostatic polarization term in all-atom force fields on the stability of preformed β-sheet oligomers. Nguyen et al (2011) observed that the initial steps of oligomer formation and the conformation space accessible to Aβ building blocks may depend on the specific force field.…”

“…Hence, proper choice of the force field is critical in all folding and aggregation studies (Freddolino, Park, Roux, & Schulten, 2009;Kia & Darve, 2013;Lindorff-Larsen et al, 2012;Nguyen, Li, & Derreumaux, 2011;Piana, Lindorff-Larsen, & Shaw, 2011;Prigozhin & Gruebele, 2013). …”