A molecular dynamics investigation of the effects of mutation on prefoldin nano actuator in inhibiting amyloid β42-dimer

Aggregation of amyloid β-peptides (Aβ) is one of the hallmarks in development of Alzheimer's disease. Recent studies show that soluble oligomers play a key role in losing synapses and in cognitive failures. Prefoldin is a molecular chaperone that identifies unfolded peptides, trapping them and preventing them from misfolding and aggregation. It is also shown to act as a nano actuator. In order to investigate the effect of mutation on the prefoldin nano actuator (PNA) performance in inhibiting the pathogenic cargo, all-atom molecular dynamics simulations were performed in an explicit solvent environment for 10 ns. Hydrophobic effects are considered as a crucial factor in attracting the cargo by nano actuator and, thus, two separate mutations were performed on PNA, namely replacing the hydrophobic amino acids on the top of any PNA tentacle. After investigating the results concerning the atomic distances, hydrogen bonds, and hydrophobic effects, the findings determined that nano actuator type 2 could attach itself to the cargo with 5 tentacles out of the six possible tentacles, which is more of an appropriate way for inhibiting it. The present research introduces the mutated PNA type 2 as an inhibitor for Aβ oligomers that could be highly effective in treating Alzheimer's disease.