Constructing conformational library for amyloid-β₄₂ dimers as the smallest toxic oligomers using two CHARMM force fields

The study of amyloid-β (Aβ) dimers as the smallest toxic aggregates in the human brain suffering from Alzheimer's disease is of great interest. The structural characterization of the dimers, which is important to rationally design inhibitors for Aβ dimerization, is limited by the low stability of these species and their high tendency to aggregate into protofibrils and amyloid fibrils. Therefore, an efficient sampling method is needed for the computational study of the Aβ dimers. In this regard, we build a conformational library of the Aβ₄₂ dimers by a new computational protocol; the blockwise excursion sampling (BES); with the CHARMM27 and CHARMM36m force fields. The CHARMM27 overestimates helix content and underestimates β-sheet content, while secondary structure content for the dimers sampled by the CHARMM36m force field is in reasonably consistent with the circular dichroism data. The CHARMM36m force field also generates more Aβ₄₂ dimers in line with experimentally measured collision cross sections values relative to the CHARMM27 force field. Our results demonstrate that the BES is an efficient protocol for fast generating a heterogeneous conformational library of the Aβ₄₂ dimers in agreement with experimental data. Having a reliable structural library for the Aβ₄₂ dimers is very important to identify binding "hot spots" of the dimers versus potential drug candidates using ensemble docking approach.