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

Numerous experimental studies indicate that amyloid beta protein (A beta) oligomers as small as dimers trigger Alzheimer's disease. Precise solution conformation of A beta 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 A beta(1-40), A beta(1-42), and A beta(1-40)(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 A beta(1-40) and A beta(1-42), striking morphological differences exist. For instance, A beta(1-42) and A beta(1-40)(D23N) have higher beta-strand propensities at the C-terminal, residues 30-42, than A beta(1-40). The D23N mutation enhances the conformational freedom of the residues 22-29 and the propensity for turns and beta-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 A beta(1-40) and the A beta(1-40)(D23N) peptides.