Quantum Mechanics and Its Implications on Melatonin Receptor Research

By Samudrapom DamMay 22 2024Reviewed by Susha Cheriyedath, M.Sc.

A study recently published in the journal Scientific Reports studied the interaction of melatonin receptors MT₁ and MT₂ with melatonin and analogs/agonists using quantum mechanical (QM), molecular dynamics, and molecular docking simulations.

Growing Importance of Melatonin

The prevalence of sleep disorders like insomnia is rising in the general population due to travel, work shifts, and mental illnesses like anxiety and depression. Pharmacological treatment for insomnia can be divided into two compound groups, including non-benzodiazepines and benzodiazepines, which are sedative-hypnotics.

However, the adverse effects of both compounds on human health have increased the interest in melatonin's therapeutic use to treat insomnia, specifically as a sleep inducer. Currently, melatonin is utilized extensively as a food supplement.

Melatonin/N-acetyl-5-methoxytryptamine, a neurohormone secreted during sleep by the pineal gland of all vertebrates, is involved in regulating circadian rhythms. The suprachiasmatic nucleus in the hypothalamus controls the melatonin secretion.

Advancements in Melatonin Research

The production of prolonged-release melatonin has gained significant attention to increase the effectiveness of supplemental melatonin. The effectiveness can also be increased using melatonin analogs and agonists like ramelteon, which are compounds that modify or mimic melatonin's effects on its receptors.

Melatonin receptors MT₁ and MT₂ are G protein-coupled receptors that mediate the effects of melatonin. Understanding the molecular interactions between these receptors and their ligands is critical for developing novel therapeutic agents.

Ramelteon is an exceptional melatonin agonist and it has been utilized in in silico studies to create new drugs using binder-based drug design. In silico studies represent an important step for developing new and more potent drugs based on existing drugs.

These studies involve protein-ligand interaction analysis using energetic calculations methodologies through QM, classical mechanics/molecular-mechanical (MM), or hybrid methods (QM/MM), which allow the evaluation of weaknesses and strengths of each ligand, proposing structural modifications that improve its receptor affinity.

The Study

In this study, researchers investigated the binding modes and affinities of three ligands, including 2-phenylmelatonin (2-PMT), ramelteon, and melatonin, with both receptors/interaction of MT₁ and MT₂ complexes with these three ligands using QM calculation and molecular dynamics and docking simulations.

The study utilized crystallographic data of the receptor-ligand complexes obtained from docking simulations as initial geometrical inputs for subsequent analyses. The density functional theory (DFT), combined with the molecular fragmentation with conjugated caps (MFCC) method, facilitated quantum binding energy calculations.

This approach allowed for the identification of key amino acids contributing to the binding affinity at melatonin receptors. Although QM calculations are effective for probing ligand-protein interactions, they come with high computational demands, especially in large biological systems.

To address this challenge, the study applied the MFCC method, which simplifies the protein into discrete amino acids by cutting peptide bonds. This allows for separate calculations of interactions between the ligand and individual residues. The sum of these individual energies provides an estimate of the total binding energy.

For the QM/MM-generalized Born surface area (QM/MM-GBSA) analysis, researchers selected frames with the lowest energy for both MT₁ and MT₂ complexes involving melatonin. Meanwhile, structures from the Protein Data Bank (PDB) with accession codes 6ME6 and 6ME325 were used for 2-PMT analyses.

The crystallographic structures of the MT2-RMT and MT1-RMT complexes were also sourced from the PDB. The interaction energies between the ligands and receptors were computed using the Gaussian 16 software package, which employs DFT. This was done after fragmenting each amino acid to better understand the interaction energies.

Furthermore, the simulations utilized the generalized gradient approximation (GGA) with the B97D functional, which is known for its efficiency and accuracy in large systems where dispersion forces are significant.

Significance of this Work

Molecular docking and dynamics simulations employed to generate MT₂-MLT and MT₁-MLT complexes revealed stronger binding to MT₁ compared to MT₂, while 2-PMT demonstrated higher affinity for both receptors compared to MLT. Key amino acids that contributed to the protein/receptor-ligand interactions include Asn162/175, Phe179/192, and Gln181/194, which were conserved in both receptors. This observation provided insights into potential therapeutic strategies. New meaningful interactions with Gly108/Gly121, Val111/Val124, and Val191/Val204 amino acids were also described.

Overall, this work improved the existing understanding of protein-ligand interactions and offered implications for future drug development, specifically for developing effective drugs to treat sleep disorders like insomnia.

Journal Reference

Sales Bezerra, K., Nobre Oliveira, J. I., Fontenele Araújo, J., Soares Galvão, D., Vogel Saivish, M., Laino Fulco, U. (2024). Quantum mechanics insights into melatonin and analogs binding to melatonin MT₁ and MT₂ receptors. Scientific Reports, 14(1), 1-17. https://doi.org/10.1038/s41598-024-59786-x, https://www.nature.com/articles/s41598-024-59786-x

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