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/Aβ42 homo-dimer and Aβ40/Aβ42 hetero-dimer in terms of free energy profile by all-atom simulations using the ff99SB force field. We have found that in the presence of Aβ40 peptide, there exists a strong tendency to form a hetero-dimer with Aβ42 peptide, suggesting that a possible co-oligomerization. Furthermore, we have investigated the effects of Aβ40 on the Aβ42 peptide. Our study also shows that in presence of Aβ40, the beta-content of Aβ42 monomer is reduced. Additionally, certain residues important for bending in Aβ42 peptide attained an increased flexibility in the presence of Aβ40. The salt-bridge destabilization also manifested the impact of Aβ40 on Aβ42 peptide as a whole. Based on this, one may expect that Aβ40 inhibits 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 Aβ40 binding induces conformational change in Aβ42. Our results suggest that co-oligomerization of Aβ isoforms may play a substantial role in Alzheimer’s disease.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have