Implicit Solvent Models and Stabilizing Effects of Mutations and Ligands on the Unfolding of the Amyloid β-Peptide Central Helix.

We have systematically evaluated the ability of molecular dynamics simulation with implicit solvation models (EEF1.1, SASA, ASPENR, SCPISM, RUSH, ACE2, GBORN, GBSW, GBMV II, FACTS) to characterize the unfolding of the amyloid beta (Aβ) peptide and the stabilizing effects of mutations and ligands. The 13-26 region of Aβ (Aβ13-26) unfolds and leads to the formation of amyloid fibrils, the causative agent of Alzheimer's disease. Stabilization of Aβ13-26 decreases Aβ polymerization as well as the formation of intermediate structures, which may also be toxic. The unfolding behavior of wild-type Aβ13-26 with an increase in temperature led us to select GBORN, GBMV II, and SCPISM for further investigation considering their ability to reproduce the stabilizing effect on the Aβ13-26 helical conformation due to mutations (V18A/F19A/F20A and V18L/F19L/F20L) and ligands (Dec-DETA and Pep1b) designed to stabilize Aβ13-26. Structural parameters (RMSD, helicity) of the peptide were used to assess the performance of the implicit solvent models with reference to previous explicit solvent simulations.