In silico identification of novel peptides as potential modulators of Aβ42 Amyloidogenesis

Alzheimer’s Disease is a neurodegenerative disease for which no cure is available at present. The presence of amyloid plaques in the extracellular space of neural cells is the key feature of this fatal disease. Amyloid-Beta (Aβ) is a 40-42 amino acid peptide and the main component of amyloid plaques. This peptide is produced by the proteolysis of Amyloid Precursor Protein by presenilin. Deposition of 42 residual Aβ peptides forms fibrils structure, leading to disruption of neuron synaptic transmission, inducing neural cell toxicity, ultimately leading to neuron death. To modulate the amyloidosis of Aβ peptides, various novel peptides have been investigated via molecular docking and molecular dynamic simulation studies. The sequence-based peptides were designed and investigated for their interaction with Aβ42 monomer and fibril using the molecular docking method, and their influence on the structural stability of target proteins was studied using molecular simulations. According to the docking results, amongst all the synthetic peptides, the peptide YRIGY (P6) has the highest binding affinity with Aβ42 fibril, and the peptide DKAPFF (P12) shows better binding with Aβ42 monomer. Moreover, simulation results also suggest that the higher the binding affinity, the better the inhibitory action. From these findings, it is suggested that both the peptides can modulate the amyloidogenesis, but peptide (P6) has better potential for the disaggregation of the fibrils, whereas peptide P12 stabilizes the native structure of the Aβ42 monomer more effectively and hence can serve as a potential amyloid inhibitor. Thus, these peptides can be explored as therapeutic agents against Alzheimer’s Disease.