title: In silico investigation on the inhibition of Aβ42aggregation by Aβ40peptide by potential of mean force study.
abstract: Recent experimental data revealed that small, soluble Amyloid beta (Aβ42) oligomers, especially dimers impair synaptic plasticity and memory leading to Alzheimer's disease. Here, we have studied dimerization of Aβ42/Aβ42homo-dimer and Aβ40/Aβ42hetero-dimer in terms of free energy profile by all-atom simulations using the ff99SB force field. We have found that in the presence of Aβ40peptide, there exists a strong tendency to form a hetero-dimer with Aβ42peptide, suggesting that a possible co-oligomerization. Furthermore, we have investigated the effects of Aβ40on the Aβ42peptide. Our study also shows that in presence of Aβ40, the beta-content of Aβ42monomer is reduced. Additionally, certain residues important for bending in Aβ42peptide attained an increased flexibility in the presence of Aβ40. The salt-bridge destabilization also manifested the impact of Aβ40on Aβ42peptide as a whole. Based on this, one may expect that Aβ40inhibits the aggregation propensity of Aβ42. Moreover, the binding free energy obtained by the molecular mechanics-Poisson-Boltzmann surface area method also revealed a strong affinity between the two isoforms thereby suggests that Aβ40binding induces conformational change in Aβ42. Our results suggest that co-oligomerization of Aβ isoforms may play a substantial role in Alzheimer's disease.
authors.affiliation: a Department of Molecular Biology and Biotechnology , Tezpur University , Tezpur 784 028 , Assam , India.
authors.forename: Mary
authors.initials: M
authors.lastname: Dutta
authors.affiliation: a Department of Molecular Biology and Biotechnology , Tezpur University , Tezpur 784 028 , Assam , India.
authors.forename: Venkata Satish Kumar
authors.initials: VSK
authors.lastname: Mattaparthi
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics; D003198:Computer Simulation; D006801:Humans; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics; D066263:Protein Aggregation, Pathological / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; aggregation inhibition; amyloid peptide; potential of mean force