Investigation of glutathione as a natural antioxidant and multitarget inhibitor for Alzheimer’s disease: Insights from molecular simulations

Abstract

Glutathione (GSH) is the most plentiful nonprotein thiol-containing substance in all kinds of cells, and plays crucial roles in the antioxidant defense system and maintaining redox homeostasis in neurons. Extensive microscopic molecular simulations with atomistic details were performed to examine GSH interaction with three proteins involved in β-Amyloid formation (BACE-1, GSK-3β, AChE). The results show that the binding of GSH to AChE is vertical and from the side of Cys residue, while for BACE-1 it was relatively horizontal. The simultaneous study of MSD and interaction energies proved that due to the stronger interaction between GSH and the active-site of BACE-1, GSH shows the least mobility in the BACE-1 containing system, also due to no binding to GSK-3β, it shows the most mobility in this system. Analyzing the radius of gyration and the molecule's inner angle showed that GSH adopts folded and extended structures in interaction with BACE-1 and AChE, respectively. Estimating binding free energy using MMPBSA calculations proved that GSH binding to BACE-1 (-16.98 kJ/mol) is thermodynamically more favorable than AChE (-8.27 kJ/mol). Contributions of active-site residues in binding free energies revealed that GSH binding into BACE-1 and AChE was controlled more dynamically and thermodynamically, respectively. Cavity size analysis showed that the accessible volume of cavities for GSH in BACE-1 and AChE is sufficient for binding. Furthermore, “adjacent pocket” and “breathing motion” types were suggested for AChE and BACE-1, respectively.