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.
Yang
Mingfeng
M
Department of Neurology, David Geffen School of Medicine, and Molecular Biology Institute and Brain Research Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Teplow
David B
DB
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D001224:Aspartic Acid / Q000737:chemistry; D003198:Computer Simulation; D006860:Hydrogen Bonding; D008969:Molecular Sequence Data; D009038:Motion; D010446:Peptide Fragments / Q000737:chemistry; D017510:Protein Folding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013499:Surface Properties; D013816:Thermodynamics
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D020033:Protein Isoforms; C075222:amyloid beta-protein (1-42); D001224:Aspartic Acid