Molecular Determinants of the Neurotoxicity of Acrylamide Through Covalent Docking

Abstract

Acrylamide is formed during food processing by Maillard reaction between sugars and proteins at high temperatures. Besides, acrylamide is used in many industries, from water waste treatment to manufacture of paper, fabrics, dyes or cosmetics. Cumulative exposure to acrylamide, either from diet or in the workplace, may result in neurotoxicity, involving three possible mechanisms: inhibition of fast axonal transport, alteration of neurotransmitter levels, and direct inhibition of neurotransmission. From the molecular point of view, acrylamide may affect protein function by forming a covalent adduct with cysteine residues via a Michael addition reaction. However, the molecular determinants of acrylamide reactivity are not completely understood and further investigation is needed. As a follow-up of previous computational studies by Carloni and coworkers [1,2], here we have performed a systematic study of the acrylamide protein targets reported so far in the literature in connection with neurotoxicity using covalent docking. Comparison with drug protein targets of acrylamide warhead-containing inhibitors was also performed. Analysis of the acrylamide-protein complexes provides insights into the determinants of cysteine reactivity, as well as the residue composition of acrylamide binding sites. This information could be used to predict other potential protein targets mediating acrylamide neurotoxicity. This project was inspired by late Dr. Ernesto Illy and funded by the Ernesto Illy Foundation. [1] de Lima, E. F., & Carloni, P. (2011). Acrylamide Binding to Its Cellular Targets: Insights from Computational Studies. Computational Biology and Applied Bioinformatics, 431. [2] Papamokos, G., Dreyer, J., Navarini, L., & Carloni, P. (2014). Trapping acrylamide by a Michael addition: a computational study of the reaction between acrylamide and niacin. Int. J. Quantum Chem., 114(9), 553-559.