title: Computational studies of Cu(II)/Met and Cu(I)/Met binding motifs relevant for the chemistry of Alzheimer's disease.
abstract: A systematic study of the binding motifs of Cu(II) and Cu(I) to a methionine model peptide, namely, N-formylmethioninamide 1, has been carried out by quantum chemical computations. Geometries of the coordination modes obtained at the B3LYP/6-31G(d) level of theory are discussed in the context of copper coordination by the peptide backbone and the S atom of a methionine residue in peptides with special emphasis on Met35 of the amyloid-beta peptide (Abeta) of Alzheimer's disease. The relative binding free energies in the gas phase, DeltaG(g), are calculated at the B3LYP/6-311+G(2df,2p)//B3LYP/6-31G(d) level of theory, and the solvation affects are included by means of the COSMO model to obtain the relative binding energies in solution, DeltaG(aq). A free energy of binding, DeltaG(aq) = -19.4 kJ mol(-1), relative to aqueous Cu(II) and the free peptide is found for the most stable Cu(II)/Met complex, 12. The most stable Cu(I)/Met complex, 23, is bound by -15.6 kJ mol(-1) relative to the separated species. The reduction potential relative to the standard hydrogen electrode is estimated to be E degrees (12/23) = 0.41 V. On the basis of these results, the participation of Met35 as a low affinity binding site of Cu(II) in Abeta, and its role in the redox chemistry underlying Alzheimer's disease is discussed.
authors.affiliation: Department of Chemistry, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Gómez-Balderas
authors.forename: Duilio F
authors.initials: DF
authors.lastname: Raffa
authors.forename: Gail A
authors.initials: GA
authors.lastname: Rickard
authors.forename: Patrick
authors.initials: P
authors.lastname: Brunelle
authors.forename: Arvi
authors.initials: A
authors.lastname: Rauk
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000577:Amides / Q000737:chemistry; D020816:Amino Acid Motifs; D001665:Binding Sites; D003198:Computer Simulation; D003300:Copper / Q000737:chemistry*; D007477:Ions / Q000737:chemistry; D008024:Ligands; D008715:Methionine / Q000737:chemistry*; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D000577:Amides; D007477:Ions; D008024:Ligands; D010455:Peptides; D003300:Copper; D008715:Methionine; D009584:Nitrogen