Pro-drug peptide and its metabolites disrupt amyloid fibrils by destabilizing salt bridge interaction and planar beta-sheet topology

The most common age-related neurodegenerative disorder, Alzheimer’s disease, is clinically characterized by continuous neuronal loss resulting in loss of memory and dementia with no cure to date. Amyloid- β (A β ) aggregates and tau protein are believed to be the causative agents of this pathogenesis. In the present study, we have investigated the effect of the Pro-Drug peptide (PDp) and its metabolites ( α -aspartyl & β -aspartyl) on the A β aggregates using atomistic molecular dynamics simulations. One of the key findings in our work is in the presence of α -aspartyl as a ligand, the salt bridges which hold the N-terminals together are completely disrupted, thus setting the N-terminals free and exposed entirely to the solvent which can make the aggregation of A β less severe. The efficiency of the ligands, which are responsible for the disruption of A β , depends on the alignment and strength of the repulsive interactions. Besides repulsive interactions, we found that there is a need for hydrogen bonding, which acts as a support for the ligand to stay in the vicinity of the aggregate. Moreover, we have noticed that one of the metabolites, namely β -aspartyl, formed more hydrogen bonds with the aggregate than the other ligands and had a different mode of action with the chains of A β due to its unique flexible kink in the backbone.