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 [<i>J. Chem. Theory Comput.</i> <b>2012</b>, <i>8</i>, 5150–5158], the structures of complexes between Aβ(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 Aβ (at His13, by Lys16 and the N-terminus; at His14, by Lys16; at His6, by Arg5). The results indicate a slight preference for His13 followed by His6 and His14, 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 (<i>E</i>°) are calculated for various Fe­(III)/Fe­(II) couples. Regardless of the point of attachment of the heme, <i>E</i>° values are approximately −0.6 V relative to the standard hydrogen electrode

The Binding of Fe(II)–Heme to the Amyloid Beta Peptide of Alzheimer’s Disease: QM/MM Investigations

The structures of complexes between Aβ(1–42) and ferroheme (Fe­(II)–heme) were determined by application of Amber and ONIOM­(B3LYP/6-31G­(d):Amber) methodology. Attachment at each of the three His residues was investigated. In each case, direct bonding of the iron to the His residue is augmented by the formation of secondary salt bridges between the carboxylate groups of the heme and positively charged residues of Aβ (at His13, by Lys16 and the N-terminus; at His14, by both Lys16 and Lys28; at His6, by Arg5) or by H-bonding and hydrophobic interactions (at His6, by Asp7 or Phe20). The results indicate a slight preference for His13 followed by His6 and His14, with the lowest eight structures lying within 36 kJ mol^–1 of each other. The methodology is not precise enough to permit a definitive statement as to the relative stabilities, nor to the absolute binding affinities, which are predicted to be less than 70 kJ mol^–1. The results bear on the question of how heme and copper may bind simultaneously to Aβ. They confirm that the <i>reduced</i> species can bind independently, Cu⁺ at His13–His14 and Fe­(II)–heme at His6