Ruđer Bošković Institute Research Data Repository
| Title (english) | Resveratrol and Its Metabolite as Potential Allosteric Regulators of Monoamine Oxidase A Activity in the Brain and Liver Under Chronic Predator Stress |
| Author | Jurica Novak Institut Ruđer Bošković |
| Scientific / art field, discipline and subdiscipline | NATURAL SCIENCES Chemistry Theoretical Chemistry |
| Abstract (english) | Resveratrol has been shown to modulate stress-related anxiety by reducing brain monoamine oxidase A (MAO-A) activity. However, the molecular mechanism underlying this neurochemical effect remains unclear. In this study, we employed in silico approaches to investigate the binding affinity of resveratrol and its predominant blood metabolite, resveratrol glucuronide, to specific sites on MAO-A. Our findings reveal the presence of an allosteric site on the enzyme that accommodates these compounds. Furthermore, in vivo experiments demonstrated that high-dose resveratrol suppresses MAO-A activity not only in the brain but also in the liver of stress-exposed rats. These in vivo results are interpreted in the context of an allosteric site on MAO-A in both the brain and liver, suggesting its potential role in mediating the interaction with resveratrol and its metabolite. |
| Methods (english) | Molecular dynamics (MD) simulations were performed using Amber 22. Protonation states of protein side chains were determined based on physiological pH conditions using the PDB2PQR web server. Ligand parameterization was carried out with the Antechamber module of Amber 22, using the GAFF2 force field for atom type assignment. Partial atomic charges were calculated using the REsP fitting method, and the protein was parametrized using the Amber ff19SB force field. To reduce computational complexity, the hydrophobic N-terminal helix (Val498–Leu524) was removed from MAO-A. The protein–ligand complexes were solvated in an octahedral water box, with a minimum distance of 12 Å from the solute to the box boundary, and neutralized by adding Na+ counterions and adjusting to a physiological salt concentration of 0.15 M NaCl. Four independent systems were simulated: MAO-A complexed with 5-HT, RES, and ROG (MAO-A:5-HT:RES:ROG), MAO-A with 5-HT and RES (MAO-A:5-HT:RES), MAO-A with 5-HT and ROG (MAO-A:5-HT:ROG), and MAO-A bound to 5-HT alone (MAO-A:5-HT). Energy minimization was performed with harmonic restraints (k = 10.0 kcal/mol/Ų) on the protein, FAD, and ligands, followed by 10,000 minimization steps using steepest descent and conjugate gradient algorithms. The systems were heated from 0 K to 310 K over 500 ps, followed by a 500 ps equilibration phase to stabilize temperature and pressure. Production MD simulations were run for 300 ns under constant pressure (1 atm) and temperature (310 K), using a Langevin thermostat with a collision frequency of 1 ps−1. The time step was set to 2 fs, with bond lengths involving hydrogen atoms constrained using the SHAKE algorithm. Non-bonded interactions were calculated using an 11 Å cutoff, and long-range electrostatic interactions were handled with the PME method. Periodic boundary conditions were applied in all directions. Simulations were performed in triplicate, with a total simulation time of 900 ns. All simulations were conducted on the Supek supercomputer at the University Computing Center (SRCE), University of Zagreb. |
| Keywords (english) | |
| Language | english |
| URN:NBN | urn:nbn:hr:241:401110 |
| Publication | 2025-03-24 |
| Geolocation | Croatia |
| Publisher | Institut Ruđer Bošković Ruđer Bošković Institute |
| Access conditions | Open access |
| Terms of use |  |
| Public note (english) | The dataset is archived as a supplement to the manuscript submitted for the review process. |
| Created on | 2025-03-20 10:24:57 |
