Effects of solvent on the structure of the Alzheimer amyloid-beta(25-35) peptide.
The free energy landscape for folding of the Alzheimer's amyloid-beta(25-35) peptide is explored using replica exchange molecular dynamics in both pure water and in HFIP/water cosolvent. This amphiphilic peptide is a natural by-product of the Alzheimer's amyloid-beta(1-40) peptide and retains the toxicity of its full-length counterpart as well as the ability to aggregate into beta-sheet-rich fibrils. Our simulations reveal that the peptide preferentially populates a helical structure in apolar organic solvent, while in pure water, the peptide adopts collapsed coil conformations and to a lesser extent beta-hairpin conformations. The beta-hairpin is characterized by a type II' beta-turn involving residues G29 and A30 and two short beta-strands involving residues N27, K28, I31, and I32. The hairpin is stabilized by backbone hydrogen-bonding interactions between residues K28 and I31; S26 and G33; and by side-chain-to-side-chain interactions between N27 and I32. Implications regarding the mechanism of aggregation of this peptide into fibrils and the role of the environment in modulating secondary structure are discussed.
Wei
Guanghong
G
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California, USA.
Shea
Joan-Emma
JE
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure*; D001665:Binding Sites; D001923:Brain Chemistry; D003198:Computer Simulation; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000648:ultrastructure*; D011485:Protein Binding; D011487:Protein Conformation; D012997:Solvents / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012997:Solvents; C074636:amyloid beta-protein (25-35); D014867:Water