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

Abstract

Amyloid beta (Aβ) peptides play a central role in the pathogenesis of Alzheimer's disease. The accumulation of Aβ peptides in AD brain was caused due to overproduction or insufficient clearance and defects in the proteolytic degradation of Aβ peptides. Hence, Aβ peptide degradation could be a promising therapeutic approach in AD treatment. Recent experimental report suggests that aminopeptidase from Streptomyces griseus KK565 (SGAK) can degrade Aβ 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 Aβ peptides. The docked complex of aminopeptidase (SGAK) and wild-type Aβ 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 Aβ 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 Aβ peptide. Hence, amino acid Glu139 of aminopeptidase (SGAK) might play an important role to degrade Aβ peptides, a causative agent of Alzheimer's disease.

Evaluation of a Possible Role of <b><i>Stigmatella aurantiaca</i></b> ACE in Aβ Peptide Degradation: A Molecular Modeling Approach

“…Hence, enzymes from microbial sources are being used to study Aβ degradation. Aβ-degrading ability of nattokinase from Bacillus subtilis natto, aminopeptidase from Streptomyces griseus K565 and cathepsin B from Xanthomonas campestris have been reported earlier Dhanavade and Sonawane, 2014;Hsu et al, 2009;Yoo et al, 2010]. This suggests that microbial enzymes could be used to understand Aβ clearance in detail at the atomic level.…”

“…Molecular docking and MD simulation are useful techniques and being used successfully to explore mo- Dhanavade and Sonawane, 2014;Jalkute et al, 2015;Parulekar et al, 2013;Tseng et al, 2007]. The predicted model of S. aurantiaca ACE was used as a receptor, whereas Aβ peptide (1AML.pdb) as a ligand molecule.…”

Identification of Angiotensin Converting Enzyme Inhibitor: An In Silico Perspective

“…The kollman united atom charges were assigned to receptor atom and charges of zinc interacting residues were manually checked. The zinc parameters like zinc radius, well depth and charges were assigned as per the earlier literature Xin and William 2003) similarly as used in our previous studies (Barage and Sonawane 2014;Dhanavade et al 2013;Dhanavade and Sonawane 2014). The active site was defined using AutoGrid (Morris et al 2009).…”

Homology modeling and molecular docking studies of ArnA protein from Erwinia amylovora: role in polymyxin antibiotic resistance

“…The docking study of ArnA protein with its substrate UDP-GlcA was carried out using PATCHDOCK online program (Duhovny et al 2002) similar to earlier studies (Barage and Sonawane 2013; Dhanavade et al 2013;Dhanavade and Sonawane 2014;Jalkute et al 2013;Parulekar et al 2013;Tseng et al 2007). PATCHDOCK is geometry based molecular docking algorithm which aims in finding docking transformations that yield good molecular shape complementarity based on its default constraints assigned for docking such as clustering RMSD, complex type, potential binding sites of receptor and distance constraints.…”