Three-Dimensional Structures of the Amyloid β Peptide (25−35) in Membrane-Mimicking Environment

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Abstract
The three-dimensional structure of amyloid β peptide (25−35), which has neurotoxic activity, in lithium dodecyl sulfate micelles was determined by two-dimensional 1H NMR spectroscopy with simulated annealing calculations. A total of 20 converged amyloid β peptide structures were obtained on the basis of 110 experimental constraints, including 106 distance constraints reduced from the nuclear Overhauser effect (NOE) connectivities and four torsion angle (φ) constraints. The atomic root mean square difference about averaged coordinates is 1.04 ± 0.25 Å for the backbone atoms (N, Cα, C) and 1.39 ± 0.27 Å for all heavy atoms of the entire peptide. The molecular structure of amyloid β peptide in membrane-mimicking environment is composed of a short α helix in the C terminal position. The three residues from the N-terminus are disordered, but the remaining eight C-terminal residues are well-ordered, which is supported by the RMSD values of the C-terminal region, Lys28-Leu34. In this region, the RMS differences from averaged coordinates are 0.26 ± 0.11 Å for the backbone atoms (N, Cα, C) and 0.77 ± 0.21 Å for all heavy atoms, which is very low compared with those for the entire peptide. The four amino acid residues from the N-terminus are hydrophilic and the other seven amino acid residues in C-terminus are hydrophobic. So, our results show that the C-terminal region of amyloid β peptide (25−35) is buried in the membrane and assumes α-helical structure, whereas the N-terminal region is exposed to the solvent with a flexible structure. This structure is very similar to membrane-mediated structure of substance P previously reported. The three-dimensional structure of a non-neurotoxic mutant of amyloid β peptide (25−35), where Asn27 is replaced by Ala, in lithium dodecyl sulfate micelles was also determined. The structure is similar to that of the wild type amyloid β peptide (25−35) in the C-terminal region, but the N-terminal flexible region is different. The structural comparison of amyloid β peptide (25−35), its non-neurotoxic mutant and substance P gives a structural basis to understand the mechanism of neurotoxicity caused by amyloid β peptide.