Folding and membrane insertion of amyloid-beta (25-35) peptide and its mutants: implications for aggregation and neurotoxicity.
The mechanisms of interfacial folding and membrane insertion of the Alzheimer's amyloid-beta fragment Abeta(25-35) and its less toxic mutant, N27A-Abeta(25-35) and more toxic mutant, M35A-Abeta(25-35), are investigated using replica-exchange molecular dynamics in an implicit water-membrane environment. This study simulates the processes of interfacial folding and membrane insertion in a spontaneous fashion to identify their general mechanisms. Abeta(25-35) and N27A-Abeta(25-35) peptides share similar mechanisms: the peptides are first located in the membrane hydrophilic region where their C-terminal residues form helical structures. The peptides attempt to insert themselves into the membrane hydrophobic region using the C-terminal or central hydrophobic residues. A small portion of peptides can successfully enter the membrane's hydrophobic core, led by their C-terminal residues, through the formation of continuous helical structures. No detectable amount of M35A-Abeta(25-35) peptides appeared to enter the membrane's hydrophobic core. The three studied peptides share a similar helical structure for their C-terminal five residues, and these residues mainly buried within the membrane's hydrophobic region. In contrast, their N-terminal properties are markedly different. With respect to the Abeta(25-35), the N27A-Abeta(25-35) forms a more structured helix and is buried deeper within the membrane, which may result in a lower degree of aggregation and a lower neurotoxicity; in contrast, the less structured and more water-exposed M35A-Abeta(25-35) is prone to aggregation and has a higher neurotoxicity. Understanding the mechanisms of Abeta peptide interfacial folding and membrane insertion will provide new insights into the mechanisms of neurodegradation and may give structure-based clues for rational drug design preventing amyloid associated diseases.
Department of Chemistry, National Central University, Jhong-Li City, Tao-Yuan County, Taiwan. hhtsai@cc.ncu.edu.tw
Hui-Hsu Gavin
HH
Tsai
Jian-Bin
JB
Lee
Sheng-Shiuan
SS
Tseng
Xiao-An
XA
Pan
Yuan-Ci
YC
Shih
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D009498:Neurotoxins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D017510:Protein Folding / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D011522:Protons; D014867:Water / Q000737:chemistry
D016229:Amyloid beta-Peptides; D050505:Mutant Proteins; D009498:Neurotoxins; D010455:Peptides; D011522:Protons; D014867:Water