Redox Properties of Met super(35) in Neurotoxic beta -Amyloid Peptide. A Molecular Modeling Study

The beta -amyloid peptide ( beta AP) is the principal component of plaque associated with the pathology of Alzheimer's disease. Part of its neurotoxicity appears to correlate with the ability of the peptide to reduce Cu super(II) and form free radicals. Both processes are dependent on the presence and oxidizability of Met super(35) in the C-terminus of the peptide but no mechanistic details on the reactions leading to Met oxidation are known. On the basis of previous studies with model peptides, we hypothesize that a one-electron oxidation of Met super(35) in beta AP is facilitated through a neighboring group effect. Complexed to Cu super(II) and/or in a lipid-mimicking environment, the solution structure of beta AP includes a large alpha -helical part. The solution NMR structure of beta AP1-40 in aqueous SDS micelles reveals an alpha -helix between residues 27 and 36, containing Met super(35). In this helical C-terminus of beta AP, the peptide bond C=O group C-terminal of Ile super(31) is located very close to the Met super(35) sulfur and could stabilize a Met super(35) sulfide radical cation through formation of an (S-O) three-electron bond. In the present paper, we have computationally validated this hypothesis using Langevin dynamics methods to determine the collision frequency of the Met super(35) thioether sulfur and the oxygen atoms of several peptide bonds in the beta AP sequence. Nanosecond time scale computations were carried out for four distinct beta AP congeners, beta AP26-40, beta AP26-36, beta AP26-40 (Ile super(31)Pro), beta AP40-26, and their respective Met super(35)-sulfur-centered cation radicals. Here, beta AP26-40, beta AP26-40(Ile super(31)Pro) and beta AP40-26 are representative fragments of the full length beta AP1-42 or beta AP42-1 sequence, respectively, whereas beta AP26-36 represents a unique beta AP sequence for which biological data are available. Initial structures of beta AP26-40, beta AP26-40(Ile super(31)Pro), and beta AP26-36 were selected to be identical to that of the beta AP26-40 or beta AP26-36 sequence in full-length beta AP1-40. As the structures of beta AP40-26 and beta AP42-1 are not known, various initial conformations such as alpha -helix and antiparallel beta -sheet were selected for beta AP40-26. Our computational results show that beta AP26-40, representative for the same sequence in full-length beta AP1-42, has the highest tendency to form (S-O) bonds between Ile super(31)C=O and Met super(35)S. We conclude