title: Structures and stabilities of Fe2+/3+ complexes relevant to Alzheimer's disease: an ab initio study.
abstract: Iron is one of the most abundant metals found in senile plaques of post mortem patients with Alzheimer's disease. However, the interaction mode between iron ions and β-amyloid peptide as well as their precise affinity is unknown. In this study we apply ab initio computational methodology to calculate binding energies of Fe(2+/3+) with the His13-His14 sequence of Aβ, as well as other important ligands such as His6 and Tyr10. Calculations were carried out at the "MP2/6-311+G(2df,2p)"//B3LYP/6-31+G(d) level of theory and solvent effects included by the IEFPCM procedure. Several reaction paths for the binding of imidazole, phenol, and the His13-His14 fragment (modeled by N-(2-(1H-imidazol-4-yl)ethyl)-3-(1H-imidazol-4-yl)propanamide) were sequentially explored. The results show that the most stable complexes containing His13-His14 and phenolate of Tyr10 are the pentacoordinated [Fe(2+)(O-HisHis)(PhO(-))(H(2)O)](+) and [Fe(3+)(N-HisHis)(PhO(-))(H(2)O)](+) compounds and that simultaneous coordination of tyrosine and His13-His14 to Fe(2+/3+) is thermodynamically favorable in water at physiological pH. Computed Raman spectra confirm the conclusion obtained by Miura et al. (  Biochemistry     2000  ,   39  ,   7024  ) that tyrosine is coordinated to Fe(3+) but do not exclude coordination of imidazoles. Finally, calculations of standard reduction potentials indicate that phenol coordination reduces the redox activity of the iron/Aβ complexes.
authors.affiliation: Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Alí-Torres
authors.forename: Luis
authors.initials: L
authors.lastname: Rodríguez-Santiago
authors.forename: Mariona
authors.initials: M
authors.lastname: Sodupe
authors.forename: Arvi
authors.initials: A
authors.lastname: Rauk
mesh_terms: D000544:Alzheimer Disease; D005290:Ferric Compounds / Q000737:chemistry*; D005296:Ferrous Compounds / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D005290:Ferric Compounds; D005296:Ferrous Compounds