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

Abstract

The interaction of aluminum ion Al(III) with polypeptides is a subject of paramount importance, since it is a central feature to understand its deleterious effects in biological systems. Various drastic effects have been attributed to aluminum in its interaction with polypeptides and proteins. These interactions are thought to be established mainly through the binding of aluminum to phosphorylated and nonphosphorylated amino acid sidechains. However, a new structural paradigm has recently been proposed, in which aluminum interacts directly with the backbone of the proteins, provoking drastic changes in their secondary structure and leading ultimately to their denaturation. In the present paper, we use computational methods to discuss the possibility of aluminum to interact with the backbone of peptides and compare it with the known ability of aluminum to interact with amino acid sidechains. To do so, we compare the thermodynamics of formation of prototype aluminum-backbone structures with prototype aluminum-sidechain structures, and compare these results with previous data generated in our group in which aluminum interacts with various types of polypeptides and known aluminum biochelators. Our results clearly points to a preference of aluminum towards amino acid sidechains, rather than towards the peptide backbone. Thus, structures in which aluminum is interacting with the carbonyl group are only slightly exothermic, and they become even less favorable if the interaction implies additionally the peptide nitrogen. However, structures in which aluminum is interacting with negatively-charged sidechains like aspartic acid, or phosphorylated serines are highly favored thermodynamically.

Aluminum and Neurofibrillary Tangle Co-Localization in Familial Alzheimer’s Disease and Related Neurological Disorders

“…In this manner, Al 3+ (aq) ions removed from nuclear DNA, may have allowed sufficient complexation with lumogallion to produce a positive intranuclear metal signal [45][46][47]. Aluminum is known to bind to the microtubuleassociated protein tau and especially upon its hyperphosphorylation forming aberrant insoluble NFTs [48]. Intraneuronal NFTs are frequently observed in the cerebral cortex of fAD, PD, and epilepsy patients, collectively prompting our study to probe their intracellular presence [7,14,17,27].…”

Aluminium toxicosis: a review of toxic actions and effects

“…Toxic effects of Al arise mainly from its pro-oxidant activity which results in oxidative stress, free radical attack and oxidation of cellular proteins and lipids (Exley, 2013). Protein polypeptides are transformed to secondary structures when Al ions interact with them through oxygen-containing amino acids, side chains and protein backbone leading to ultimate denaturation (Mujika et al, 2018) or conformational or structural alteration (Exley et al, 1993;Zatta et al, 2005;Exley, 2006) as in β-amyloid.…”

“…Oxidative stress, lipid peroxidation Kattab et al, 2010;Exley, 2013;Abd-Elhady et al, 2013;Zhang et al, 2016;Yang et al, 2018;Yu et al, 2019 Pro-inflammatory: organ inflammation in lung, intestine, heart, and testis Fogarty et al, 1998;Verma et al, 2007;Lerner, 2007;Exley, 2013;Taiwo, 2014;de Chambrun et al, 2014;Gherardi et al, 2016;Martinez et al, 2017;Hangouche et al, 2017 Immunosupression: induces lymphocyte apoptosis and dysfunction, inhibits lymphocyte proliferation, causes macrophage dysfunction Nordal and Dahl, 1988;Kammalov et al, 2011;She et al, 2012;Zhu et al, 2014;Zhuang et al, 2016;Xu et al, 2018;Yu et al, 2019 Protein denaturation and transformation Exley et al, 2006;Mujika et al, 2018 Enzymatic stimulation or inhibition Ohsaka and Nomura, 2016 Metabolic impairment: impairs glycolysis and Kreb's cycle; promotes lipid and protein oxidation Xu et al 1990;Mailloux et al, 2006 Genotoxicity: reduced cell proliferation and differentiation, dysneurogenesis Nam et al, 2014 Amyloidogenic and anti-amyloidolytic Sakamoto et al, 2006;Xu et al, 2016 Acts as metalloestrogen, promotes proliferation and migration of breast cancer cells Bakir and Darbre, 2015;Darbre, 2016 Induces teratogenesis causing foetal and neonatal defects Malekshah et al, 2005;Wang et al, 2012;El Mazoudy and Bekhet, 2016 Disrupts mineral metabolism of Fe, P, Ca, Zn, Cu by altering intestinal absorption and cellular uptake…”

Aluminum effects on marine phytoplankton: implications for a revised Iron Hypothesis (Iron–Aluminum Hypothesis)

“…Third, Al can substitute for other cations (e.g., Mg) in biological systems, reacting with biomolecules to form strong bonds that are slow to dissociate (Exley and Mold 2015;Williams 1996). In addition, Al can induce the formation of strong structures in a wide range of peptides, through binding amino acid sidechains (Mujika et al 2017). Binding to the peptide backbone has also been considered (Mujika et al 2014;Song et al 2014) but is less favored (Mujika et al 2017).…”

“…In addition, Al can induce the formation of strong structures in a wide range of peptides, through binding amino acid sidechains (Mujika et al 2017). Binding to the peptide backbone has also been considered (Mujika et al 2014;Song et al 2014) but is less favored (Mujika et al 2017). As a result, Al may make organic carbon more difficult to decompose, again leading to greater and longer sequestration in the ocean depths.…”