Amyloid peptide Aβ40 inhibits aggregation of Aβ42: Evidence from molecular dynamics simulations

Abstract

Effects of amyloid beta (Aβ) peptide Aβ(40) on secondary structures of Aβ(42) are studied by all-atom simulations using the GROMOS96 43a1 force field with explicit water. It is shown that in the presence of Aβ(40) the beta-content of monomer Aβ(42) is reduced. Since the fibril-prone conformation N∗ of full-length Aβ peptides has the shape of beta strand-loop-beta strand this result suggests that Aβ(40) decreases the probability of observing N∗ of Aβ(42) in monomer state. Based on this and the hypothesis that the higher is the population of N∗ the higher fibril formation rates, one can expect that, in agreement with the recent experiment, Aβ(40) inhibit fibril formation of Aβ(42). It is shown that the presence of Aβ(40) makes the salt bridge D23-K28 and fragment 18-33 of Aβ(42) more flexible providing additional support for this experimental fact. Our estimation of the binding free energy by the molecular mechanics-Poisson-Boltzmann surface area method reveals the inhibition mechanism that Aβ(40) binds to Aβ(42) modifying its morphology.