The Binding of Fe(II)–Heme
to the Amyloid Beta
Peptide of Alzheimer’s Disease: QM/MM Investigations
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Abstract
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<sup>–1</sup> 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<sup>–1</sup>. 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<sup>+</sup> at His13–His14 and Fe(II)–heme at His6