Computational investigation of BMAA and its carbamate adducts as potential GluR2 modulators

Abstract

ABSTRACTBeta-N-methylamino-L-alanine (BMAA) is a potential neurotoxic non-protein amino acid, which can reach the human body through the food chain. When BMAA interacts with bicarbonate in the human body, carbamate adducts are produced, which share high structural similarity with the neurotransmitter glutamate. It is believed that BMAA and its L-carbamate adducts bind in the glutamate binding site of ionotropic glutamate receptor 2 (GluR2). Chronic exposure to BMAA and its adducts could cause neurological illness such as neurodegenerative diseases. However, the mechanism of BMAA action and its carbamate adducts bound to GluR2 has not been yet elucidated. Here, we investigate the binding modes and the affinity of BMAA and its carbamate adducts to GluR2 in comparison to the natural agonist, glutamate, to understand whether these can act as GluR2 agonists. Initially, we perform Molecular Dynamics (MD) simulations of BMAA and its carbamate adducts bound to GluR2 to examine the stability of the ligands in the S1/S2 ligand-binding domain of the receptor. In addition, we perform alchemical free energy calculations to compute the difference in the free energy of binding of the beta-carbamate adduct of BMAA to GluR2 compared to glutamate. Our findings indicate that carbamate adducts of BMAA and glutamate remain stable in the binding site of the GluR2 compared to BMAA. Additionally, alchemical free energy results reveal that glutamate and the beta-carbamate adduct of BMAA have comparable binding affinity in the GluR2. These results provide a rationale that BMAA carbamate adducts may be in fact the modulators of GluR2 and not BMAA itself.