ABSTRACT
Aim:
Mitochondriogenesis refers to the process of creating and maintaining mitochondria, which plays an essential role in cellular metabolism. Mitochondrial processes such as energy generation, the response to oxidative stress, and cell death are all tightly regulated by enzymes. The flavonoid molecule malvidin-3-glucoside (M3G), which may be found in a wide variety of fruits and vegetables, has been shown to improve mitochondrial activity. However, the precise enzymes that mediate M3G’s effect on mitochondriogenesis are yet unknown.
Method:
Here, we used in silico molecular modeling tools to look at how enzymes contribute to mitochondriogenesis after M3G administration. We used computational methods to discover candidate target enzymes known to interact with M3G and play important roles in mitochondrial physiology. Molecular docking was conducted to measure the binding affinity and stability of the M3G-enzyme complexes. The found enzymes’ structural and functional features were analyzed using bioinformatics techniques, and the predicted functional implications of their interaction with M3G were formulated.
Result:
Our goal in doing these studies was to understand better how M3G regulates mitochondriogenesis by the action of altering SIRT-1, AMPK, and PGC-1α via M3G.
Conclusion:
In sum, our findings provide light on the molecular pathways by which M3G influences mitochondriogenesis. Furthermore, experimental validation of the discovered enzymes and their interactions with M3G may aid in the development of therapeutic approaches to improve mitochondrial function and cellular health.
KEYWORDS: In silico modeling, good health and well-being, malvidin-3-glucoside, mitochondriogenesis, molecular docking
INTRODUCTION
The creation and maintenance of healthy mitochondria, known as mitogenesis, is essential for normal cellular metabolism, energy generation, and survival. Mitochondriogenesis is regulated in large part by enzymes, which affect processes as diverse as energy generation, the response to oxidative stress, and cell death.[1,2,3] Mitochondrial function regulation genes include SIRT-1, AMPK, and PGC-1α.[4] The flavonoid component malvidin-3-glucoside (M3G), which is present in many fruits and vegetables, has been shown to improve mitochondrial activity.[5] However, the precise enzymes that mediate M3G’s effect on mitochondriogenesis are yet unknown.
In silico molecular modeling approaches have recently emerged as strong tools for studying the interactions of tiny compounds and enzymes, yielding important insights into the mechanisms underpinning biological processes. Potential target enzymes may be identified, binding affinities with substances can be evaluated, and functional ramifications of interactions predicted, all via the use of computational methods. To further understand how enzymes contribute to mitochondriogenesis after M3G therapy, we planned to use in silico molecular modeling tools.[6,7] To determine which enzymes interact with M3G and play important roles in mitochondrial processes, we turned to computational approaches. Molecular docking and molecular dynamic simulations were conducted to evaluate the stability and binding affinity of the M3G-enzyme complexes. Our goal in doing these studies was to better understand the various pathways by which M3G affects mitochondriogenesis and cellular health.
In silico modeling work may provide light on the molecular pathways through which M3G affects mitochondrial function. Understanding the regulatory mechanisms by which M3G affects mitochondriogenesis requires the identification and characterization of the enzymes involved. Additionally, the discovered enzymes and their interactions with M3G serve as possible targets for experimental validation, opening the door for further investigation into M3G’s therapeutic potential in a wide range of cellular and metabolic illnesses linked to mitochondrial malfunction.
METHODS AND MATERIALS
Protein target preparation
The Protein Data Bank (PDB) provided the specific proteins such as SIRT-1, AMPK, and PGC-1α (4cff, 5unj, 4zzh) target. The desired protein was created using the Discovery Studio Visualizer 2020. The water molecules residing inside the protein molecules were examined and eliminated where necessary. Additionally, the bound ligands and ions were removed. In general, hydrogen atoms are absent from PDB proteins. As a consequence, the protein was given hydrogen atoms in order to transform it into a conventional protein. Additionally, hydrogen atoms play a part in docking research. Finally, protein manufacturing was finished using optimization and minimization techniques.
Ligand preparation
The ligand, malvidin-3-glucoside (CID: 11249520), was sourced from the PubChem database. The Discovery studio visualizer 2020 was used to build the compounds, and it was modified to ensure the ligand’s lower energy isomer. The ligand molecules then underwent molecular docking tests after energy reduction.
Molecular docking
Molecular docking tests were carried out with the aid of the Discovery Studio application. For the docking simulations, the produced protein structures (SIRT-1, AMPK, and PGC-1α) and the ligand malvidin-3-glucoside were used. To forecast the attachment configurations and affinities of the ligand within the binding regions of the target proteins, the docking software used algorithms [Figure 1]. In order to create probable binding poses, the docking computations took into account a number of variables, such as protein–ligand interactions, shape complementarity, and electrostatic potentials. The probable binding postures were created by the docking program, which then ranked them according to their binding energies or scores. These ratings provide an idea of the interaction projected potency between the ligand and the protein target. In order to determine probable binding mechanisms and interactions between malvidin-3-glucoside and the target proteins (SIRT-1, AMPK, and PGC-1α), the docking findings were analyzed and interpreted. Understanding the probable binding affinities and interactions of malvidin-3-glucoside with the target proteins required molecular docking research. These details clarified the potential mechanisms of action and offered an understanding of the molecular processes behind the actions of malvidin-3-glucoside on the chosen protein targets. In conclusion, modifying the protein structures, including the removal of water molecules and the addition of hydrogen atoms and Kollman Charges, was required to prepare the protein target. Using PubChem, ligand production was carried out, and energy-saving methods were used. Using Discovery Studio software, molecular docking experiments were carried out to determine the affinities and binding mechanisms of malvidin-3-glucoside for the target proteins. This thorough approach made it easier to look into potential interactions and gave valuable information about the molecular processes that underlie malvidin-3-glucoside impact on the chosen protein targets.[8]
Figure 1.
A(II), B(II), C(II): 3D interaction of AMPK, PGC-1α, SIRT-1 molecules
RESULTS
After acquiring data, it can build log table, 2D interaction, and 3D interaction [represented in Figures 1, 2 and Tables 1 and 2]. Malvidin-3-glucoside plays an important role in mitochondrial activity. The docking score for all three proteins is more than -4.5, which is significant score.
Figure 2.
A(I), B(I), C(I): 2D interaction of AMPK, PGC-1α, SIRT-1 with malvidin-3-glucoside
Table 1.
A (I), B (I), C (I): A log table that shows affinity and RMSD value
| A (I) mode|affinity|dist from best mode | |||
|---|---|---|---|
| | (kcal/mol) | rmsd l.b.| rmsd u.b. | |||
| -----+------------+----------+---------- | |||
| 1 | -6.9 | 0.000 | 0.000 |
| 2 | -6.8 | 0.524 | 2.132 |
| 3 | -6.6 | 15.182 | 19.797 |
| 4 | -6.6 | 15.176 | 19.717 |
| 5 | -6.5 | 14.799 | 19.094 |
| 6 | -6.5 | 2.159 | 6.037 |
| 7 | -6.5 | 31.156 | 35.278 |
| 8 | -6.5 | 31.721 | 35.063 |
| 9 | -6.4 | 29.884 | 33.789 |
|
| |||
| B (I) mode|affinity|dist from best mode | |||
|
| |||
| | (kcal/mol) | rmsd l.b.| rmsd u.b. | |||
| -----+------------+----------+---------- | |||
| 1 | -6.6 | 0.000 | 0.000 |
| 2 | -6.6 | 0.372 | 2.151 |
| 3 | -6.5 | 16.184 | 19.528 |
| 4 | -6.4 | 22.352 | 26.285 |
| 5 | -6.3 | 21.787 | 25.996 |
| 6 | -6.3 | 22.493 | 26.470 |
| 7 | -6.3 | 21.818 | 26.056 |
| 8 | -6.3 | 22.037 | 25.163 |
| 9 | -6.2 | 1.747 | 6.228 |
|
| |||
| C (I) mode|affinity|dist from best mode | |||
|
| |||
| | (kcal/mol) | rmsd l.b.| rmsd u.b. | |||
| -----+------------+----------+---------- | |||
| 1 | -8.5 | 0.000 | 0.000 |
| 2 | -8.5 | 0.025 | 2.010 |
| 3 | -8.4 | 1.712 | 7.646 |
| 4 | -8.4 | 1.707 | 7.434 |
| 5 | -8.3 | 14.964 | 18.937 |
| 6 | -8.3 | 14.970 | 18.847 |
| 7 | -8.2 | 18.067 | 21.616 |
| 8 | -8.2 | 13.096 | 17.813 |
| 9 | -8.2 | 13.561 | 17.258 |
Table 2.
Comparison of molecular docking results of malvidin-3-glucoside on AMPK, PGC-1α, and SIRT-1 family members
| Result analysis | Visuvalaization software | Protein | Ligand | Docking score | Aminoacid residue |
|---|---|---|---|---|---|
| Auto dock 1.5.7 | Discovery software | AMPK | Malvidin-3- glucoside | -6.9 | Conventional Hydrogen Bond: ARG C: 442, GLU C: 541, GLN F: 80 Conventional Hydrogen Bond: LYS D: 268 |
| PGC-1α | -6.6 | Conventional Hydrogen Bond: GLN A: 445, HIS A: 397 Pi -Anion: GLU A: 315 | |||
| SIRT-1 | -8.5 | Conventional hydrogen bond: ARG A: 424, SER A: 365 Carbon hydrogen bond: THR A: 368, GLN A: 421 |
Table A (I) indicates docking score between AMPK and malvidin-3-glucoside. This table shows affinity and RMSD value. Affinity of this protein is -6.9 for zero RMSD value.
Table B (I) indicates docking score between PGC-1α and malvidin-3-glucoside. This table shows affinity and RMSD value. Affinity of this protein is -6.6 for zero RMSD value.
Table C (I) indicates the docking score between SIRT-1 and malvidin-3-glucoside. This table shows affinity and RMSD values. The affinity of this protein is -8.5 for zero RMSD value.
DISCUSSION
In silico molecular modeling is a potent computer method for studying molecule–enzyme interactions and gaining an understanding of their functions in biological processes. The effects of malvidin-3-glucoside on mitochondrial biogenesis were investigated using in silico molecular modeling to isolate the part played by individual enzymes (PGC-1α, AMPK, and SIRT1).[9] PGC-1α, AMP-activated protein kinase, and SIRT1 are three of the most important enzymes in controlling mitochondriogenesis.[10] Important nodes in a regulatory system for the balance of metabolism include metabolic indicators like SIRT1 and AMPK, controllers of the function of the primary regulator of mitochondrion, PGC1. Together, these factors account for many of the success we have had in combating metabolic illnesses through changes to our diet and exercise routine.[4] To learn more about how malvidin-3-glucoside interacts with these enzymes, we used in silico molecular modeling simulations. Based on our findings, malvidin-3-glucoside binds to PGC-1α, AMPK, and SIRT1 with a high affinity. Mitochondriogenesis may be affected by malvidin-3-glucoside’s binding to certain enzymes involved in the process. Malvidin-3-glucoside, in particular, was shown to interact with PGC-1α, a transcriptional coactivator known to control the expression of genes involved in mitochondrial biogenesis, according to our modeling results. Malvidin-3-glucoside binds to PGC-1α, which may improve its activity and stimulate mitochondrial gene expression and mitogenesis.
Polyphenols bind to AMPK and may increase its phosphorylation and activation, boosting mitochondrial biogenesis. Activation of AMPK may drive mitochondrial biogenesis and improve mitochondrial function.[11] Increased longevity and enhanced mitochondrial activity have been linked to SIRT1 activation.[12] Our modeling also indicated that malvidin-3-glucoside may initiate AMPK, a critical energy sensor and regulator of cellular metabolism. Our modeling also showed that malvidin-3-glucoside interacted with SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase involved in cellular energy metabolism and stress response. Malvidin-3-glucoside binds to SIRT1, which may increase its deacetylase activity and result in the deacetylation of mitochondrial genesis-related target proteins.
CONCLUSION
The enzymes PGC-1α, AMPK, and SIRT1 might have a role in modulating the action of malvidin-3-glucoside on mitochondrial biogenesis, according to in silico molecular modeling research. Malvidin-3-glucoside’s potential to stimulate mitochondrial biogenesis via its binding to these enzymes has been extensively studied. These results help explain how malvidin-3-glucoside improves mitochondrial activity and cellular metabolism at the molecular level. Malvidin-3-glucoside may enhance mitochondrial function by increasing the expression of mitochondrial genes, stimulating mitochondrial biogenesis, and activating AMPK and SIRT1.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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