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.
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.
Mingfeng
M
Yang
David B
DB
Teplow
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