Amyloid beta-protein monomer folding: free-energy surfaces reveal alloform-specific differences.

Alloform-specific differences in structural dynamics between amyloid beta-protein (Abeta) 40 and Abeta42 appear to underlie the pathogenesis of Alzheimer's disease. To elucidate these differences, we performed microsecond timescale replica-exchange molecular dynamics simulations to sample the conformational space of the Abeta monomer and constructed its free-energy surface. We find that neither peptide monomer is unstructured, but rather that each may be described as a unique statistical coil in which five relatively independent folding units exist, comprising residues 1-5, 10-13, 17-22, 28-37, and 39-42, which are connected by four turn structures. The free-energy surfaces of both peptides are characterized by two large basins, comprising conformers with either substantial alpha-helix or beta-sheet content. Conformational transitions within and between these basins are rapid. The two additional hydrophobic residues at the Abeta42 C-terminus, Ile41 and Ala42, significantly increase contacts within the C-terminus, and between the C-terminus and the central hydrophobic cluster (Leu17-Ala21). As a result, the beta-structure of Abeta42 is more stable than that of Abeta40, and the conformational equilibrium in Abeta42 shifts towards beta-structure. These results suggest that drugs stabilizing alpha-helical Abeta conformers (or destabilizing the beta-sheet state) would block formation of neurotoxic oligomers. The atomic-resolution conformer structures determined in our simulations may serve as useful targets for this purpose. The conformers also provide starting points for simulations of Abeta oligomerization-a process postulated to be the key pathogenetic event in Alzheimer's disease.