Rules governing metal coordination in clusters from Aβ-Zn(II) complexes from quantum mechanical calculations

Transition metals directly contribute to the neurotoxicity of the aggregates of the amyloid-forming A$\beta$ peptide. The understanding and rationalisation of the coordination modes of metals to A$\beta$ amyloid is therefore of paramount importance to understand the capacity of a given metal to promote peptide aggregation. Experimentally, multiple A$\beta$-metal structures have been resolved, which exhibit different modes of coordination in both the monomeric and oligomeric forms of A$\beta$. Although Zn(II) metalloproteins are very abundant and often involve cysteine residues in the first coordination shell, in the case of A$\beta$-Zn(II), though, Zn(II) is coordinated by glutamic/aspartic acid and/or histidine residues exclusively, making for an interesting case study. Here we present a systematic analysis on the underlying chemistry on A$\beta$- Zn(II) coordination, where relative stabilities of different coordination arrangements indicate that a mixture of Glu/Asp and His residues is favoured. A detailed comparison between different coordination shell geometries show that, in the aqueous phase, tetrahedral coordination is favoured in general. Our calculations show an interplay between dative covalent interactions and electrostatics which explains the observed trends. Multiple structures deposited in the Protein Data Bank support our findings, suggesting that the trends found in our work may be transferable to other Zn(II) metalloproteins with this type of coordination.