Molecular Docking - Science method

You need to add Ag in the autodock file: refere here:https://autodock.scripps.edu/how-to-add-new-atom-types-to-the-autodock-force-field/

Sahil Lohana in MGL Tools, you can write the whole complex as a single file when you are going through docking analysis (through Analyze tab). However, you can also save each molecule (Receptor and Ligand) individually through MGL Tools by opening them one at a time. There are also other tools available like OpenBabel (GUI and Command line versions) which you can use to convert the files from one format into another. I would suggest you to read documentation for MGL Tools about analyzing results and saving complex file or watch Youtube videos about Autodock results analysis in MGL Tools. Hope this helps.

use this app which automatically energy minimized the ligands while preparing https://sourceforge.net/projects/mzdock/

Nail Besli Yes you are absolutely correct about the change in conformation of the protein when bound to two different molecule types. However, if you have no structural information available for the conformation with the activator, but have the information for the inhibitor binding.

Molecular dynamics can be a good way to gain some insights of how these conformations change when your protein is unbound (WT), bound to inhibitor and bound to the activator.

This comparative analysis of the structural transitions on a free energy landscape may provide you with detailed conformational transitions that are playing roles. It might be external factors too like salt concentration, pH temperature and so on.

Further, you may use this information to validate your results experimentally and if the changes are adequate you can measure them using fluorescence spectroscopy and circular dichroism spectroscopy experiments.

You can use AutoDockTools for the same

Regards

Sorry my silly question, where should I add "atom_par Se 4.21 0.291 14.000 -0.00110 0.0 0.0 0 -1 -1 4 # Non H-bonding"?

Mussarat Jabeen

Yeah absolutely! Gaussian is used for optimizations and theoretical chemical reactivity parameters. As per your concern, you can publish an article using Pyrx-based docking with valid explanations.

Dear Ibrahim M. Ibrahim ,

You can use Zdock and ClusPro server as well to see if the results are useful.

The version of Python you are using has a memory leak and is therefore not compatible with the Autodock4.py script. Somehow the version of Python you have consumes all the memory on your machine when you run Autodock4.py, you have to fix that first before trying to continue with Docking.

Are you using Windows? You can try reinstalling python on your machine or if not, you can use WSL and try to run everything from there.

Good luck!

It depends, if those het atoms are necessary for your proteins to interact, then nope, otherwise remove them. If these het atoms are part of crystallization process, you should remove them.

You need to prepare your system as well, make sure all atoms are present, geometry is optimized and protein is minimized. Pay attention to missing parts and secondary structure mismatch, just in case.

Once your proteins are ready, then go for docking.

Last point, avoid blind docking, search literature and see if binding residues are reported (if not for this protein, may be for homologous protein), and used them as starting point.

Ceren Orhan Thank you for pointing out your findings about OS processors. If MGL Tools can't be installed, it'll be recommended he considers other docking tools like Maestro (Schrodinger) or MOE.

However, I think John Paul Sese Tosoc should give us an update in regards to his post. If solved, HOW? This would help future computational chemists looking for such solution.

Dear Aaryan,

There are many journals that include docking studies as part of their aims and scope; however, some of them are certainly behind paywalls. Therefore, if you wish to find one without APCs, you must first eliminate some journals from these publishers, namely MDPI and Frontiers.

Some other journals, such as Elsevier, Taylor & Francis, and Wiley, may allow you to publish your paper without paying APCs. Here are a few examples:

- Journal of Molecular Graphics and Modelling (Elsevier, ISSN: 1093-3263)

- Journal of Molecular Structure (Elsevier, ISSN: 0022-2860)

- Journal of Biomolecular Structure and Dynamics (Taylor & Francis, ISSN: 0739-1102)

- Molecular Simulation (Taylor & Francis, ISSN: 0892-7022)

- Journal of Molecular Recognition (Wiley, ISSN: 0952-3499)

However, bear in mind that nowadays, conducting docking studies alone is not usually sufficient for publication, especially in these prominent publishers. Unless you add further validation to your results, such as performing in vitro experiments or carrying out MD simulations, your manuscript will most likely be rejected. Therefore, I suggest you consider employing these approaches or look for another journal (preferably Q3-Q4) that might be able to publish your work in its current state.

Please follow this link: GROMACS Tutorials (mdtutorials.com)

Hi Pablo Cavagnero

It probably mainly depends on the surface area of your substrate and/or how many ligand binding sites there are. Hopefully, literature can help you with this information. Either way, I suppose the aim is to obtain as many ligand conformations for each bound pose. After a generating a certain number of docked poses, you might notice that the ligand conformations and their binding energies start to appear similar. In my opinion, this is where you stop generating more poses.

If I were you, I would read the literature first. If that does not provide me with sufficient information, I would take an approximate guess on the number of poses (preferably a high number) by looking at the surface area and electrostatics of the substrate and ligand, and also the time / resources required to perform this calculation.

All the best.

Dear Dr. Punet Kumar , You can use network pharmacological analysis to get your target protein.

Few ligand docking software allows you to explore multiple poses for a given ligand in a specific binding site. While CB-Dock2 might not provide this feature directly, you can try other docking tools like AutoDock or GOLD, which allow for flexible ligand docking and can provide multiple poses.

Here are some popular tools you can consider:

It is important to carefully analyze the results from these tools and consider using multiple tools to cross-validate the predicted binding sites.

I had this issue - I used 7-zip to unpack teh folder instead and then it was fine

To achieve protein-protein interaction through molecular docking, the following steps are involved:

1.Preparation: Prepare the protein structures to be docked by removing water molecules, adding any missing atoms, and optimizing the structures.

2.Selection of Docking Software: Choose appropriate molecular docking software or tools that utilize algorithms to predict the best possible binding conformations between the proteins.

3.Docking Algorithm: Apply the selected docking algorithm, often based on scoring functions and search algorithms. These algorithms explore the possible orientations of the proteins and evaluate their compatibility based on various criteria, such as shape complementarity, electrostatic interactions, and hydrogen bonding.

4.Binding Site Identification: Identify the binding sites or regions on the proteins where interaction is likely to occur. These sites can be determined through experimental data, protein structures, or predictive algorithms.

5.Docking Simulation: Run the docking simulation by allowing the proteins to move and explore different conformations to find the most energetically favorable or probable binding configuration.

6.Scoring and Analysis: Evaluate and score the generated docking poses to identify the most promising protein-protein interaction models. Higher scores typically indicate better binding affinity and stability.

7.Validation: Validate the predicted protein-protein interactions using experimental techniques like biochemical assays, mutagenesis studies, or structural analysis (e.g., X-ray crystallography, NMR) to confirm the accuracy of the predicted complexes.

Aaryan Gupta Hi

In autodock you have to change the parameter file and add the metal and its coordinate in parameter .dat file, I've attached below the parameter link for metals.

Thank you for your response. Is it possible to dock one ligand, and then, taking into account the influence of the first ligand, proceed to dock the second ligand (same ligand) in the presence of the first one? @Sargol Mazraedoost

I have a similar question here. After generating the binding sites using sitemap and lets say l get 5 binding sites. From these 5 binding sites how do l know which one is the best site and select that one?!

Hi K. Sai Pavithra ,

In the first place, I would present all the ligands you have explored and show the chemical differences between them, followed by a presentation of your target (if this is not so relevant, you can just comment it); additionally, you could also include a brief remark of the methodology you used.

Then, I would include a table with the Z-score values provided by Vina, and also some pictures of the most relevant poses brought. Here, you can also explain the differences and the main interactions you found and considered as relevant and interesting for your binding mode. Furthermore, you can build a picture by overlapping different poses and explain slightly the possible binding mode of the ligands.

Finally, the presentation could end by showing final remarks as a summary, and some conclusions about what you obtained, personal thoughts about it or also you may propose questions that lead to the active participation of the public (maybe they can help you to largely explore the way you took in your research).

Bests!

Dear Vishal Zambre,

Make sure about your PDB and ligand preparation before Docking. Issues in ligand preparation, such as incorrect atom typing, atom order, or charges can lead to flipped poses. Also check symmetry and chirality, because in some cases, docking algorithms may produce inverted chiral centers. Ensure correct stereochemistry in both co-crystallized and docked poses.

Adjust flexibility, scoring, and search parameters for accurate poses and also avoid over-optimization to prevent false positives. If the binding pocket undergoes substantial conformational changes upon ligand binding, prefer flexible docking or induced fit docking approaches.

You can verify input coordinates and formats for both co-crystallized and docked structures. Additionally, try alternative docking software to assess if the issue persists, as different algorithms may yield varied results.

Conduct post-docking minimization or molecular dynamics simulation to refine docked poses and address inaccuracies introduced in the docking process.

Carefully examine these aspects to identify the cause of flipped poses and implement necessary corrective measures.

Thank You

Hello. In order to dock a protein whose 3D structure is not available on the uniprot site, you must model its 3D structure, for this there are many servers such as Itasser, Quark, and Robetta, and after evaluating and measuring your 3D structure, you can do the docking by Servers like Cluspro, Zdock or Hdock

it's important to consider specific proteins that play crucial roles in the survival and reproduction of microorganisms. Enzymes involved in cell wall synthesis: Proteins like penicillin-binding proteins (PBPs) are crucial for bacterial cell wall formation.

DNA gyrase and topoisomerases: Involved in DNA replication and repair, these are essential targets for antimicrobial compounds.

Ribosomal proteins: Targeting bacterial ribosomes can disrupt protein synthesis. Utilize databases like the Protein Data Bank (PDB) to find crystal structures of your selected proteins. Molecular docking predictions should be validated through in vitro and in vivo experiments.for in vitro evaluation you can use microorganisms directly.

When this type of error occurs to me, I prepare the ligand file again using the openbabel software, without making any modifications... just rewriting it.

example:

obabel -ipdbqt lig.pdbqt -opdbqt -Olig.pdbqt

Typically, such a solution works.

Approach to describing and interpreting the results of molecular docking:

1. Binding pose analysis: The docking software typically generates multiple binding poses, representing different orientations and conformations of the ligand within the binding site. Analyze the binding poses to identify the most favorable or energetically favorable pose based on scoring functions, such as binding affinity or energy.

2. Interaction analysis: Investigate the specific interactions between the ligand and the target protein. This involves examining hydrogen bonds, electrostatic interactions, hydrophobic interactions, and other non-covalent interactions. Identify key residues in the binding site that contribute significantly to ligand binding.

3. Binding affinity estimation: Docking programs often assign a scoring or energy value to each pose, which can be used to estimate the binding affinity. Lower energy or more negative scores generally indicate stronger binding. However, it's essential to interpret these scores cautiously and consider their limitations, as they may not always correlate perfectly with experimental binding affinities.

4. Validation and comparison: Validate the docking results by comparing them with experimental data, if available. This can involve comparing known ligand-protein complexes or experimental binding affinities. Assess the accuracy and reliability of the docking predictions based on their agreement with experimental findings.

Regarding determining the biological activity of a compound, it's important to note that molecular docking alone cannot definitively determine biological activity. However, it can provide valuable insights and hypotheses regarding potential ligand-target interactions. The docking results can guide further experimental studies, such as binding assays, biochemical assays, or in vivo experiments, to validate and confirm the predicted binding interactions and assess the compound's biological activity.

In summary, molecular docking results provide information about ligand binding modes, interaction patterns, and estimated binding affinities. While they can offer valuable insights into ligand-target interactions, experimental validation is required to confirm the biological activity of a compound. Molecular docking serves as a useful tool in the early stages of drug discovery and optimization, aiding in the design and selection of potential lead compounds for further development.

Hope it helps:credit AI

The situation you describe is distinct from a competitive inhibitor. It would be an allosteric inhibitor that competes with an allosteric activator, but is not itself an activator (like a receptor antagonist). These compounds would bind somewhere other than in the substrate binding site. Compounds that bind in the substrate binding site are almost always competitive inhibitors.

Alternatively, the inhibitor could compete with a co-substrate that is required for the reaction but is not converted into the product. An example would be with certain metal ions. A metal ion such as Mg²⁺, Zn²⁺ or Mn²⁺ might be involved in the reaction. This is often the case when the substrate is a nucleotide or nucleic acid, for example. Other metal ions, such as Cd²⁺ might act as inhibitors by displacing the normal metal ion but not making the appropriate interactions to act as the co-substrate. However, this is not a likely scenario when you screen so-called drug-like molecules, because they are much larger than metal ions. A more realistic possibility would be competition with a noncovalently bound organic cofactor.

Have you checked the protein structure and have you energy minimized it???

Is there any particular reason for using CB DOCK2 for initiating the docking protocol???

You can use AutoDockTools for the same which is an open source software.

Regards

Yes, it is possible to present docking results without additional support from the results of molecular dynamics (MD) simulations. However, increasingly, reviewers of manuscripts under consideration for publication in journals are requesting MD simulations to help bolster conclusions derived from docking results. It is, of course, also helpful (and often necessary) to have experimental results pertaining to the binding of ligands to macromolecular targets and to use docking and/or MD simulations to provide explanations for the observed experimental results.

Use chem3d and upload the sdf file after that you can convert it into pdb file.

To visualize a protein-protein docked complex in LigPlus, you need to first rename the chains of the proteins. As, initially, both chains are named 'Chain A', before visualization, you need to change the chain names. To rename the chains, PyMol can be used.

Thank you so much Nor Farrah Wahidah Ridzwan & Mokhamad Fahmi Rizki Syaban had been confused for quiet a long time without knowing this. I will do the needful and try generating the interactions.

You may try the standalone version of HADDOCK then:

Also, you may try FlexPepDock from Rosseta. Maybe that one is easier for running a whole library

Bests,

You can use this split_SDF.py python package to spilt your SDF files into smaller chunks

MOE is also a very reliable software for protein-ligand docking, I've used it several times and I use Schrodinger too. So u can use it if you need an alternative to Schrodinger

The term "good" is relative. Just like Dr. Rajesh Pal mentioned, one strategy is to dock another compound which is either a known binder (ligand) or a known non-binder. Then you can compare if -5 Kcal/mol is "good" binding energy or not.

As a general rule, ligands that binding successfully to deep binding pockets or cavities have large-negative binding energies. While ligands that bind successfully to shallow pockets (for example during protein-peptide interactions) tend to have small-negative binding energies.

Uddipta Ghosh Dastidar Thank you very much.

RAM= 32 GB or higher

Processor= Intel core i7 or higher

High-end GPU instead of CPU

Linux OS

I would suggest using a workstation instead of a laptop.

Hello!

Both charges are based on electron density and add the partial charges on the protein system which provide more accuracy in calculations.

Hello Piyush. I am not able to completely understand your problem. Did you download a protein with an ion "nd" that you want to re-dock with using pyrx? Or did you separately downloaded the ion file and want to perform docking with the unbound protein?

Use Discovery Studio, it's a handy tool to convert sdf to pdb.

MOE provides a command-line interface (CLI) for performing molecular docking, which can be accessed using the "moe-dock" command. The "moe-dock" command takes a number of input files and parameters, which can be specified on the command line or in a parameter file.

To create a docking grid in MOE, you can use the "moe-grid" command. This command takes a receptor structure file and generates a grid file that can be used for docking. The command also takes a number of parameters that control the size and spacing of the grid.

Here is an example command to generate a docking grid using MOE's CLI:

```

moe-grid -receptor receptor.mol2 -grid ligand.grid -spacing 0.5 -range 16

```

Command to generate grid file named "ligand.grid" with a spacing of 0.5Å and a range of 16Å around the receptor molecule in the file "receptor.mol2".

MOE also provides a number of scripts for performing molecular docking, including Python scripts. These scripts are available in the "scripts" directory of the MOE installation. One of the most commonly used scripts is "moe-docking.py", which performs docking using a receptor and ligand file, and generates a set of docked poses.

Here is an example command to run "moe-docking.py" using the command line:

```

$MOE_HOME/scripts/moe-docking.py -receptor receptor.mol2 -ligand ligand.mol2 -grid ligand.grid -o docked.mdb

```

This command docks the ligand molecule in the file "ligand.mol2" to the receptor molecule in the file "receptor.mol2", using the grid file "ligand.grid" generated earlier. The output is written to a MOE database file named "docked.mdb".

Hope it helps!!

Credit: Mostly AI tool

To identify major and minor groove binding in the case of molecular docking of A-DNA with a ligand/complex, you can analyze the groove binding using PyMOL or Discovery Studio 2021 Client software. Here's a general approach you can follow:

Using PyMOL:

Using Discovery Studio 2021 Client software:

Remember, the specific steps and features available may vary slightly depending on the version and capabilities of the software you are using.

You can use PLIP (https://plip-tool.biotec.tu-dresden.de/plip-web/plip/index) to get details regarding non-bonded interactions between two macro molecules. Alternatively you can use the native software tools to find out about such interactions.

Open to collaborate. DM if interested.

I had the same issue which made me exhausted while doing flexibke docking. Thank God, got the free trial version of schrodinger package which solved many problems. I will suggest you to plz change your approach

Alireza Mohebbi Thank you for the idea, it helps. I've changed the chain ID using Pymol before docking process.

By "linker" I assume you mean "ligand"?

Assuming that's what you meant, I did separate the two files but encountered errors when I tried to generate the topology of the ligand because of incorrect bond order.

That is precisely why I posed my question here. If someone can tell me how I can correct the bond orders post-docking, I will then be able to generate the necessary topologies and continue with the molecular dynamics simulations following the standard protocols.

Thankyou so much for your suggestion! I will definitely check the procedures that you recommended.

It is an interesting thing, and in case you want to inversely prove that the two proteins do not interact is difficult. The docking algorithms focus on few parameters like shape, charges, hydrophobicity and then see whether the bound form has lower energy/intact. This way they create multiple different poses and then evaluate them based on physical model and rank them.

You can take any two proteins, and they will interact (theoretically).

Just to prove that 2 proteins do not interact, take multiple known protein pairs that do not interact (for sure) and then dock to see the score/binding affinity. This will give you a population of false-positive.

Take another set and do the same and get the scores for true-positive.

Now, dock your two proteins and see how different the dock score of your interested proteins is? Is it statistically significantly different from True-positive or False-positive? Simple T-test can be used.

From here, you can argue that the proteins do (not) interact. You can do it with two or three different softwires (mostly are available as web server).

Once done, can you please share your finding here. Good luck.

Yes, autodock 4.2 can do it but requires an additional script for such task.

You can consult 10.1007/s11030-022-10523-4 for other software

This is a experience I would share; you can simply find a pdb file from a database which has a calcium ion and copy-past its atom types and coordinates into your pdf file. However, the ion may not be resides within the appropriate site within the protein. For fixing such complication you can manually change x y z coordination by changing 1.000, 2.000, and 3.000 values in the following line of CA structure in a pdb file;

HETATM 1 CA CAL A 1 1.000 2.000 3.000 1.00 0.00 CA

For docking you may use DOCK Blaster server, but bling docking dose not determine the correct binding site.

BUT THIS JOURNAL IS TAKING CHARGE/FEE FOR PUBLISHING ARTICLE.

PLEASE SUGGEST REPUTED JOURNAL WHICH WILL NOT TAKE CHARGE.

CB-Dock uses AutoDock Vina for molecular docking. To interpret the results generated by the server, it is important to understand the meaning of these pieces of information. The Vina score is a measure of the predicted binding affinity between the ligand and the protein, where a lower value indicates a stronger binding affinity. The cavity size refers to the size of the binding pocket or cavity on the protein's surface where the ligand is predicted to bind. The docking center is the central point within the binding cavity where the ligand is predicted to bind. The docking box size is the size of the box that encloses the binding cavity and is used to limit the search area during the docking process.

Based on the Vina score and cavity size, the model with a Vina score of -8.8 and a cavity size of 774 appears to be the best among the models you listed. This model has the strongest predicted binding affinity (as indicated by the lowest Vina score) and a moderate-sized cavity that may be suitable for accommodating a ligand of appropriate size and shape.

I hope this has been helpful.

By examining the structure and referring to the publication about the structure, you can see that the statin binding site is located at interfaces between monomers. Therefore, you need to retain at least two of the chains that form a given binding site for the inhibitor.

Dear Kritika,

Drawing nanosheets for molecular docking research necessitates a three-dimensional (3D) material structure. However, PubChem only shows the material's two-dimensional (2D) structure. As a result, before you can conduct molecular docking experiments, you must first build the 3D structure of the nanosheets.

Using a software application that can convert 2D structures into 3D structures, such as Avogadro or Open Babel, to construct the 3D structure of MoS2 nanosheets is one technique. These tools can take the MoS2 2D structure and build a 3D model suitable for molecular docking research.

Another option is to build the 3D structure of MoS2 nanosheets using computational approaches. This can be accomplished through the use of molecular dynamics simulations or density functional theory (DFT) calculations. These methods, as opposed to basic conversion tools, can yield more accurate 3D structures of nanosheets.

Regards,

Satyendra

There are several tools and servers available for DNA-protein site-specific docking, including:

Hi,

1) VINA is fairly good at docking.

2) You should also try DoGSiteScorer, PockDrug, and other relevant resources to predict the binding site residues. This can give you a better clue, plus it also predicts the druggness of the site.

Therefore, is this the correct methodology to take a certain binding affinity value to act as a cut-off and then proceed with physiochemical properties to filter out best-hit compounds? "YES (with caution); as the binding affinity is crude and not rigorous"

You can also perform clustering to see where the highest number of ligands bound with protein and it aligns with your predicted active/binding site.

Docking scores predict binding affinity, not the effect of the binding on the protein function. There are cases when a small structural difference does not affect the binding affinity but changes the mode of action from inhibition to activation or vice versa.

Maksim Romanyuk could you please try downloading version 1.16 from here https://www.cgl.ucsf.edu/chimera/download.html

Adil Parvez Hi

You have to go tool option-> click on receptor-ligand interaction and select ->view interaction that's it.

There are several insilico tools available for tracking the conformational changes in the model complex after protein-peptide molecular docking. Here are some of them:

These insilico tools can provide valuable insights into the conformational changes in the protein-peptide complex after molecular docking and aid in the design of new drugs or peptides targeting specific proteins.

Both Autodock Vina tools and Discovery Studio Visualizer are capable of preparing protein and ligand structures for docking simulations, but they have different features and capabilities.

Autodock Vina Tools is a software package specifically designed for preparing structures for docking with Autodock Vina. It includes tools for preparing ligand and receptor structures, assigning atom types, adding charges and other necessary parameters, and creating input files for docking simulations. Autodock Vina Tools is highly optimized for use with Autodock Vina, which is one of the most widely used docking programs.

Discovery Studio Visualizer, on the other hand, is a more general-purpose molecular visualization and analysis software package. It includes a wide range of tools for preparing and analyzing molecular structures, including tools for geometry optimization, energy minimization, and charge assignment. It can also be used for preparing structures for docking simulations, but it is not specifically optimized for use with any particular docking program.

In general, if you are planning to use Autodock Vina for docking simulations, it may be more efficient to use Autodock Vina Tools for preparing your structures, since it is specifically designed for this purpose. However, if you are using a different docking program, or if you need to perform more general molecular modeling tasks, Discovery Studio Visualizer may be a better choice. Ultimately, the choice between these tools will depend on your specific needs and preferences.

check this tutorial for AMDock https://github.com/Valdes-Tresanco-MS/AMDock-win/wiki/4.5.3-Input-a-customized-AD4-parameter-file

Hi,

just add the following lines (also to AD4.1_bound.dat):

atom_par Na 3.98 0.030 12.000 -0.00110 0.0 0.0 0 -1 -1 1 # Sodium

atom_par As 4.23 0.309 13.000 -0.00110 0.0 0.0 0 -1 -1 1 # Arsenic

Hi, an interesting question, I once attended a meeting where the author has first docked and then he did NMR studies, and surprisingly, the NMR pose was in 2nd cluster, not in the first cluster as he was expecting. So, he went for the 2nd cluster.

If you have already known structural information, you should use them as the standard, and compare your docking results against them. Molecular docking can be wrong/flawed and should not, in principal, use blindly.

In you case, I suggest to go for the 5th or 9th which one is closer to your structural studies rather than using lowest energy.

Up

You're welcome.