In silico investigation on the inhibition of A(42) aggregation by A(40) peptide by potential of mean force study

Recent experimental data revealed that small, soluble Amyloid beta (A(42)) oligomers, especially dimers impair synaptic plasticity and memory leading to Alzheimer's disease. Here, we have studied dimerization of A(42)/A(42) homo-dimer and A(40)/A(42) 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 A(40) peptide, there exists a strong tendency to form a hetero-dimer with A(42) peptide, suggesting that a possible co-oligomerization. Furthermore, we have investigated the effects of A(40) on the A(42) peptide. Our study also shows that in presence of A(40), the beta-content of A(42) monomer is reduced. Additionally, certain residues important for bending in A(42) peptide attained an increased flexibility in the presence of A(40). The salt-bridge destabilization also manifested the impact of A(40) on A(42) peptide as a whole. Based on this, one may expect that A(40) inhibits the aggregation propensity of A(42). 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 A(40) binding induces conformational change in A(42). Our results suggest that co-oligomerization of A isoforms may play a substantial role in Alzheimer's disease.