Distinct Morphologies for Amyloid Beta Protein Monomer: Aβ1-40, Aβ1-42, and Aβ1-40(D23N)

Numerous experimental studies indicate that amyloid beta protein (Aβ) oligomers as small as dimers trigger Alzheimer's disease. Precise solution conformation of Aβ monomer is missing since it is highly dynamic and aggregation prone. Such a knowledge is however crucial to design drugs inhibiting oligomers and fibril formation. Here, we determine the equilibrium structures of the Aβ1-40, Aβ1-42, and Aβ1-40(D23N) monomers using an accurate coarse-grained force field coupled to Hamiltonian-temperature replica exchange molecular dynamics simulations. We observe that even if these three alloforms are mostly disordered at the monomeric level, in agreement with experiments and previous simulations on Aβ1-40 and Aβ1-42, striking morphological differences exist. For instance, Aβ1-42 and Aβ1-40(D23N) have higher β-strand propensities at the C-terminal, residues 30-42, than Aβ1-40. The D23N mutation enhances the conformational freedom of the residues 22-29 and the propensity for turns and β-strands in the other regions. It also changes the network of contacts; the N-terminal (residues 1-16) becoming more independent from the rest of the protein, leading to a less compact morphology than the wild-type sequence. These structural properties could explain in part why the kinetics and the final amyloid products vary so extensively between the Aβ1-40 and the Aβ1-40(D23N) peptides.