Varoglutamstat Inhibits the Dimerization of the Aβ_25–35 Fragment in Aqueous Solution

The self-aggregation of amyloid-beta (Aβ) peptides is strongly associated with Alzheimer's disease. In this study, the influence of the small varoglutamstat compound on the conformations of the FAβ_25-35 dimer was extensively characterized by using MD simulations. The influence of the ligand on the conformation of the FAβ_25-35 dimer was studied during the first 10.0 μs. However, its real influence was clarified when the trajectory was extended to 20.0 μs. This indicates that the investigation of a ligand inhibiting Aβ requires a longer MD simulation than previously thought. The ligand changes ensemble properties by reducing the formation of nonbonded intermolecular contacts and β-content. Although varoglutamstat has weak binding to the FAβ_25-35 dimer, the free energy landscape is impacted in shape, free energy barrier, and number of minima. Notably, it is found that the population of the amyloid-competent dimer structure is substantially reduced upon ligand addition. Furthermore, the change from β-hairpin conformation to antiparallel structure may occur through a transition state forming a random coil conformation.