High-Resolution Structures of the Amyloid-β 1–42 Dimers from the Comparison of Four Atomistic Force Fields

Abstract

The dimer of the amyloid-β peptide Aβ of 42 residues is the smallest toxic species in Alzheimer’s disease, but its equilibrium structures are unknown. Here we determined the equilibrium ensembles generated by the four atomistic OPLS-AA, CHARMM22*, AMBER99sb-ildn, and AMBERsb14 force fields with the TIP3P water model. On the basis of 144 µs replica exchange molecular dynamics simulations (with 750 ns per replica), we find that the four force fields lead to random coil ensembles with calculated cross-collision sections, hydrodynamics properties, and small-angle X-ray scattering profiles independent of the force field. There are, however, marked differences in secondary structure, with the AMBERsb14 and CHARMM22* ensembles overestimating the CD-derived helix content, and the OPLS-AA and AMBER99sb-ildn secondary structure contents in agreement with CD data. Also the intramolecular beta-hairpin content spanning residues 17–21 and 30–36 varies between 1.5% and 13%. Overall, there are significant differences in tertiary and quaternary conformations among all force fields, and the key finding, irrespective of the force field, is that the dimer is stabilized by nonspecific interactions, explaining therefore its possible transient binding to multiple cellular partners and, in part, its toxicity.

How accurate are your simulations? Effects of confined aqueous volume and AMBER FF99SB and CHARMM22/CMAP force field parameters on structural ensembles of intrinsically disordered proteins: Amyloid-β42in water

“…Overall, our findings agree with those by Carballo-Pacheco and Strodel 65 as well as those by Derreumaux and co-workers 73 when we use a smaller confined aqueous volume for water. However, results change abruptly using a larger confined aqueous volume, indicating that the simulations of Ab 42 in an aqueous solution environment utilizing an explicit water model need to be revised critically using varying confined aqueous volumes.…”

“…Even though Ab 42 is a disordered peptide with mostly random coil structure, the formations of a-helical and b-strand structures have been directly linked to the conformational favorability of the Ab peptide as well as to the rigidity of its C-terminal region using experimental and theoretical tools (see, for example, refs. 22,73,74,[89][90][91] ). Furthermore, b-strand formation, which was also detected in monomeric Ab, was shown to play crucial roles in the oligomerization and fibrillation mechanisms of Ab (see, for example, refs.…”

“…For instance, Man et al tested most recently the impact of varying force field parameters on the structures of Ab 42 using only one water volume utilizing an explicit water model (TIP3P) without considering confined aqueous volume effects. 73 Moreover, Stroedel and co-workers simulate the structures of Ab 42 using only one water volume utilizing an explicit water model. In one of their recent studies, they used only 3,621 -3,636 water molecules to solvate the structures of Ab 42 and to study the impact of varying force field parameters on the simulated structures of Ab 42 .…”

Exploiting a Mechanical Perturbation of Titin Domain to Identify How Force Field Parameterization Affects Protein Refolding Pathways

“…Due to the complexity of the parameterization process, various force fields are not guaranteed to exhibit the same effect on biomolecular behavior. [13][14][15][16][17][18][19][20][21][22][23][24][25][26] This has been seen previously when modifica-tions to torsion angle parameters have been shown to impede folding and generate incorrect structures. [27][28][29] Thus force field variations can affect sensitive biomolecular processes such as protein folding pathways.…”

Spontaneous Self-assembly of Amyloid β (1-40) into Dimers

“…However, unlike the dimer conformations identified here, their dimers contained significant βstructure content. More recent findings from the same group (86) show that the dimers structures are more diverse and do not contain a large extent of β-structure, and that the dimer is stabilized by nonspecific interactions. The low β-structure content is in agreement with our findings, and also can explain the role of structural plasticity in the interactions of Aβ oligomers with binding partners and ultimately their toxicity.…”