Question for presentation

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Question for presentation

Postby sreiling » Thu Feb 13, 2014 9:17 am

Hello Sargis! I am enjoying writing my thesis (and I really mean it), especially since PyRx has made my life a bit easier, in this regard. However, I need some advice. I would like to do two things with the docking poses I have saved as either sdf or individual PDBs:

1) Calculate possible bonds (and their distances) between the ligand, and residues in my enzyme's binding pocket. I would like to include Van Der Waals forces, in this. Is PyMOL a good program for this? If not, do you have any recommendations? LigPlot, maybe? I know that I probably have to eyeball pi-stacking between the ring of a ligand, and that of any residues of interest (e.g. tyrosine), correct? In other words, what is the best way to go about doing such analysis? I have read many many papers on homologues to my enzyme, and the authors do great analysis from docking studies, and I know which residues are important to look at, but they don't necessarily explain this aspect. What constitutes an important "interaction", which I take to mean "bond" of some sort, in the literature? Is it strictly bond distance combined with atom-types constituting the bond?

2) I want to make screenshots to put in my thesis. That is easy. However, the only way I know to do this now, is to load up my original PDB inPyMOL, then load up my docking pose PDB (or pick one from the sdf file). From here, I change the original enzyme PDB to a cartoon figure, and leave the docking pose PDB as sticks. However, I would like to leave it all as stick figures. The problem is, that my original PDB still has the residues that are also present in the saved docking pose PDB (e.g. there will be two copies of "Tyr31" in the 3D space, in different conformations). I would go ahead and delete the residues on the original PDB, and attach the residues of the docking file PDB to the frame, but I am afraid that would shift the residues a bit, and as a result skew the H-bonding or whatever bonding that I wish to observe, as mentioned in question number 1, above. So what do you suggest?

Thank you for any, and all help, Sargis!

ps- Would you like to be Skyped in to the public portion of my thesis defense? Hehe...
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Re: Question for presentation

Postby sargis » Fri Feb 14, 2014 4:02 am

Hello Scott! Thank you for the message and best wishes with your thesis. Glad to hear PyRx makes it a bit easier to write your thesis.

Regarding visualizing interactions with ligands, PyMOL is indeed a good program for that. I don't have much experience with PyMOL, but I know that it's one of the best molecular visualization programs and it's used in most publications. I haven't used LigPlot; I only know that it produces nice interaction diagrams. You can also use ADT, which can produce similar interaction diagrams in 3D. As to what constitutes an important "interaction": I think it's a subjective matter of interpretation, that's why they don't necessarily explain this aspect. It's possible to modify different residues and do some sort of measurements to see how it influences biochemistry of protein-ligand interaction, but I haven't seen any docking studies that would back their claims on the importance of different "interaction" with experimental measurements. That being said, you can use PyMOL, ADT or LigPlot and describe what you think are important interaction.

For 2), changing the original enzyme PDB to a cartoon figure, and leave the docking pose PDB as sticks sounds good. If you have results from rigid docking, maybe you can visually inspect what residues make close contacts with your ligand and then see how it changes when you make specific residues flexible. I don't see why the procedure you described would shift the residues a bit; perhaps if you can visualize that, it would help me and others see what's going on.

I'll be honored to be Skyped in to the public portion of your thesis defense, but don't worry about that. I know you have many more important things to worry about.

Best Wishes with your thesis defense!

ps: The discussion about important "interaction" reminds me on the recent study that questions benefits of mammogram screening http://www.cnn.com/2014/02/12/health/ma ... g-benefits. Mammogram screening is way more real than any of the virtual protein-ligand interactions, and still you''ll get different answers depending who you ask.
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Re: Question for presentation

Postby sreiling » Sat Apr 26, 2014 6:20 am

Sargis, I did it! I successfully defended on Thursday! I mentioned PyRx, and put you in my credits and "thanks" slide. I also gave an outline of PyRx functionality (and which functions I used) in the body of the presentation. Again, thanks for PyRx, and your time!

I still have some loose ends to tie-up to officially receive the degree, but it's an incredible feeling to get past that final hump.

However, I may have more communications with you, because this field of computational molecular biology/bioinformatics (or however one wants to denote it) is just fascinating. I enjoy the fact that it draws from all of the branches of science, includes programming and even high-level math, if one chooses. It can be as challenging as one wants!

As an aside, have you ever modeled an uncompetitive inhibitor, without an experimentally derived structure? I performed some kinetic assays with a number of scaffold inhibitors for one of he enzymes I have been working with, and it came back with data that hinted it as being uncompetitive. So, it may bind with the substrate, in the binding pocket. However, I have no idea of the mode, and have no crystal structure data.
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Re: Question for presentation

Postby sargis » Sun Apr 27, 2014 2:07 am

Congrats, that's a great news! Glad to hear you have successfully defended your thesis and thank you for using PyRx. Thank you also for the outline of PyRx functionality and the credits.

I'll be happy to have more communications with you. Computational molecular biology/bioinformatics is indeed fascinating. I remember reading A farewell to bioinformatics, which has generated interesting discussions here and there. Nevertheless, the number and quality of various computational methods in molecular biology is only going to increase and this is great time to be in this field. There is good and bad in any job. Computational biology is one of the few areas where one can combine love for biology and computers together and there is always something new and interesting to learn.

Regarding modeling an uncompetitive inhibitor, without an experimentally derived structure, I haven't done any work in this area. I have tried shape-based alignment of molecules, but haven't made any progress there. I would be interested to hear what are some of the open-source tools that would be useful to integrate or implement in PyRx.

Again, thank you for using PyRx and congrats on your successful thesis defense!
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