Insights into the molecular interactions between aminopeptidase and amyloid beta peptide using molecular modeling techniques

Amyloid beta (A beta) peptides play a central role in the pathogenesis of Alzheimer's disease. The accumulation of A beta peptides in AD brain was caused due to overproduction or insufficient clearance and defects in the proteolytic degradation of A beta peptides. Hence, A beta peptide degradation could be a promising therapeutic approach in AD treatment. Recent experimental report suggests that aminopeptidase from Streptomyces griseus KK565 (SGAK) can degrade A beta peptides but the interactive residues are yet to be known in detail at the atomic level. Hence, we developed the three-dimensional model of aminopeptidase (SGAK) using SWISS-MODEL, Geno3D and MODELLER. Model built by MODELLER was used for further studies. Molecular docking was performed between aminopeptidase (SGAK) with wild-type and mutated A beta peptides. The docked complex of aminopeptidase (SGAK) and wild-type A beta peptide (1IYT.pdb) shows more stability than the other complexes. Molecular docking and MD simulation results revealed that the residues His93, Asp105, Glu139, Glu140, Asp168 and His255 are involved in the hydrogen bonding with A beta peptide and zinc ions. The interactions between carboxyl oxygen atoms of Glu139 of aminopeptidase (SGAK) with water molecule suggest that the Glu139 may be involved in the nucleophilic attack on Ala2-Glu3 peptide bond of A beta peptide. Hence, amino acid Glu139 of aminopeptidase (SGAK) might play an important role to degrade A beta peptides, a causative agent of Alzheimer's disease.