Molecular determinants of acrylamide neurotoxicity through covalent docking

Area of Science:

• Biochemistry
• Neuroscience
• Computational Chemistry

Background:

• Acrylamide (ACR) is a neurotoxicant formed during food processing and used in various industries.
• ACR exerts toxicity via covalent modification of cysteine residues in neuronal proteins.
• The precise molecular mechanisms and protein targets of ACR neurotoxicity are not fully elucidated.

Purpose of the Study:

• To identify and analyze acrylamide protein targets associated with neurotoxicity.
• To investigate the molecular determinants of acrylamide reactivity with cysteine residues.
• To evaluate the utility of covalent docking as a tool for predicting ACR-protein interactions.

Main Methods:

• Literature compilation of known acrylamide protein targets.
• Systematic covalent docking studies of acrylamide with protein cysteine residues.
• Analysis of the influence of neighboring amino acids on acrylamide binding affinity.

Main Results:

• Acrylamide binding to cysteine is favored by nearby positively charged amino acids (lysine, arginine).
• Covalent docking scores effectively differentiate primary and secondary acrylamide modification sites.
• Structural insights into ACR-protein complexes suggest functional consequences, particularly for non-enzymatic proteins.

Conclusions:

• Covalent docking is a valuable computational approach for predicting acrylamide's reactivity with cysteine residues.
• This method can help identify novel protein targets mediating acrylamide-induced neurotoxicity.
• Understanding these interactions is crucial for assessing and mitigating ACR health risks.