J Chem Theory Comput. 2012 Dec 11;8(12):5150-8. doi: 10.1021/ct300716p. Epub 2012 Sep 26.

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

Journal of chemical theory and computation

Samira Azimi, Arvi Rauk

PMID: 26593204 DOI: 10.1021/ct300716p

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(-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 reduced species can bind independently, Cu(+) at His13-His14 and Fe(II)-heme at His6.

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• Journal Article