Irreversible Denaturation of Proteins through Aluminum‐Induced Formation of Backbone Ring Structures

Abstract

A combination of ab initio calculations, circular dichroism, nuclear magnetic resonance, and X-ray photoelectron spectroscopy has shown that aluminum ions can induce the formation of backbone ring structures in a wide range of peptides, including neurodegenerative disease related motifs. These ring structures greatly destabilize the protein and result in irreversible denaturation. This behavior benefits from the ability of aluminum ions to form chemical bonds simultaneously with the amide nitrogen and carbonyl oxygen atoms on the peptide backbone.

Aluminum's preferential binding site in proteins: sidechain of amino acids versus backbone interactions

“…Moreover, two Al(III)-peptide structures were optimized (see Figure 1): i) Al(III) interacts with the peptide bond carbonyl oxygen (referred to as State I) and ii) Al(III) interacts with the peptide bond carbonyl oxygen and the deprotonated N atom (referred to as State II). For these two structures, the coordination shell of Al(III) was fulfilled based on the three coordination shells considered for the hydrated Al(III), that is: i) pentacoordinated with one hydroxide in the coordination shell (as in ref [13], no subscript added) ii) pentacoordinated and shell completed with water molecules (the "1,5" subscript added) and iii) hexacoordinated and shell completed with water molecules (the "0,6" subscript added). All the structures are represented in Figure 1 and the optimized geometries illustrated in Figure 2.…”

“…In the present paper, we apply different quantum methods to determine the thermodynamics of aluminum binding to the backbone of proteins. To do so, we consider a series of model structures based on the work of Song et al, [13] and we compare their binding energies to model structures in which aluminum is interacting with the sidechain of an amino acid. We also compare our results with previous calculations of model polypeptides in which the interaction is mediated through a variety of sidechains, including phosphorylated serines, known biological lowmolecular-mass (LMM) chelators such as citrate, and a variety of phosphate molecules.…”

“…As a first approach, we follow the proposal of Song et al, [13] who employed a small model to analyze the interaction between Al(III) and the backbone of a peptide (an alanine capped by H atoms, shown in Figure 1…”

“…On the other hand, the authors took as a reference in aqueous environment a 4 ] 2+ species. [13] However, both experiments [23,24] and computational studies [17] indicate that Al(III) shows preference towards being octahedral in aqueous solution, either coordinated to six water molecules, i.e.…”

“…More recently, Song et al, [13] have suggested a new paradigm in the type of aluminum-protein interaction. They have proposed aluminum could directly interact…”