Fe(III)-Heme Complexes with the Amyloid Beta Peptide of Alzheimer's Disease: QM/MM Investigations of Binding and Redox Properties of Heme Bound to the His Residues of Aβ(1-42)

Pursuant to our previous paper [J. Chem. Theory Comput. 2012, 8, 5150-5158], the structures of complexes between A beta(1-42) and ferriheme (Fe(III)-heme-H2O) were determined by application of Amber and ONIOM-(B3LYP/6-31G(d):Amber) methodology. Attachment at each of the three His residues was investigated. As well as direct bonding of the iron to the His residue, bonding is augmented by formation of secondary salt bridges between the carboxylate groups of the heme and positively charged residues of A beta (at His 13, by Lys16 and the N-terminus; at His14, by Lys16; at His6, by Arg5). The results indicate a slight preference for His 13 followed by His6 and His 14, with the lowest 10 structures lying within 30 kJ mol(-1) of each other. The absolute binding affinities are predicted to be approximately 30-40 kJ mol(-1). Standard reduction potentials (E degrees) are calculated for various Fe(III)/Fe(II) couples. Regardless of the point of attachment of the heme, E degrees values are approximately -0.6 V relative to the standard hydrogen electrode.