2 research outputs found
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 (FeÂ(III)–heme–H<sub>2</sub>O) were determined by application of Amber and ONIOMÂ(B3LYP/6-31GÂ(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<sup>–1</sup> of each other. The absolute binding affinities
are predicted to be approximately 30–40 kJ mol<sup>–1</sup>. Standard reduction potentials (<i>E</i>°) are calculated
for various FeÂ(III)/FeÂ(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
(FeÂ(II)–heme) were determined by application of Amber and ONIOMÂ(B3LYP/6-31GÂ(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 FeÂ(II)–heme at His6