Coupled Homology #290

electronicsbyjulie · 2023-07-04T17:47:30Z

This is mutually exclusive with #286 and #289 as there would be many conflicts due to copied code.

Trying something different. If we can do homologous conformational changes to ORs based on the OR51E2 cryo-EM, then why not for the mTAAR9 cryo-EMs and various other experimental models of coupled GPCRs. The placement of the G protein can be part of the homology model.

electronicsbyjulie · 2023-07-05T02:35:43Z

The IDs of the removed PDBs are:

2ydo
3rfm
5g53
2rh1
4ldo
P38405

electronicsbyjulie · 2023-07-05T06:06:58Z

It is downloading the PDBs, opening the receptors and alpha subunits, uprighting the assemblies, and outputing them beautifully to example coupled PDBs.

Next step will be to examine the mTAAR9-hGNAS2 examples having different ligands, and see how much they vary in order to estimate whether "soft" docks will be necessary. Soft docking is far more CPU intensive than normal docking. A small variance between models may mean that soft docking would not be important, but ORs have "softer" binding pockets than TAARs.

Then there will have to be some kind of layer between the coupled PDBs and the PrimaryDock app, or else a new feature internal to the app, to do the conformational change of the OR in parallel to the coupled PDB and its inactive counterpart. This functionality will first apply the changes to activate the inactive OR for a given G protein, then fine-tune the receptor's shape to optimize G protein contact, optimize internal contacts such as Y6.55-D/E45.51, and minimize clashes. Finally, the custom tuned receptor will be ready for dock.

primaryodors · 2023-07-05T18:53:02Z

The results are looking great!

Recall that we want to create coupled versions of the odor receptor PDBs and store them in the pdbs/coupled/ folder, then do docking against those. The idea is for the coupled models to be reusable for all ligands. Therefore, they wouldn't be generated on the fly by a function of bin/primarydock.

Also, hydrogenate means hydrogenate. Not add a bunch of non-coplanar heavy pi atoms that cause warnings in the program output.

…dors/primarydock into ssepeq-coupled-homology

electronicsbyjulie · 2023-07-07T02:52:17Z

This is almost ready, just have to figure out how best to fit in reshaping the receptors to minimize internal clashes and clashes with the G protein.

It's making promising looking predictions so far. I'm thinking of readying this for merge and starting on a UI feature that would display predictions on the odorant page in the web app.

#293

electronicsbyjulie · 2023-07-11T03:21:22Z

Test succeeded.

primaryodors · 2023-07-11T15:28:29Z

src/classes/aminoacid.cpp

@@ -699,12 +714,6 @@ AminoAcid::AminoAcid(const char letter, AminoAcid* prevaa, bool minintc)
    Atom* CA = get_atom("CA");
    Atom* CB = get_atom("CB");

-    if (CA && CB)


Does deleting this block have a favorable effect on clashes in peptides?

primaryodors · 2023-07-11T15:29:29Z

src/classes/aminoacid.cpp

@@ -1958,12 +1969,57 @@ void AminoAcid::hydrogenate(bool steric_only)
        if (!oxt->get_bond_between(C)) oxt->bond_to(C, 1);
    }

+    int i, j, k, l, n;
+
+    if (residue_no == 349)


Looks like some debug code didn't get removed.

primaryodors · 2023-07-11T15:30:51Z

src/classes/constants.h

@@ -328,7 +335,7 @@
 #define _dbg_null_flexions 0
 #define _dbg_repack 0
 #define _dbg_multiflex 0
-#define _dbg_homology 0
+#define _dbg_homology 1


All debug constants are to be turned off for production.

primaryodors · 2023-07-11T15:33:14Z

src/classes/atom.cpp

@@ -1170,7 +1170,7 @@ Bond* Atom::get_bond_by_idx(int bidx)

 void Atom::consolidate_bonds()
 {
-
+    //


What does this function do? If it is not in use, we should remove it.

primaryodors · 2023-07-11T15:44:25Z

src/classes/intera.cpp

    return anomaly;
 }

 float InteratomicForce::covalent_bond_radius(Atom* a, Atom* b, float cardinality)
 {
    if (!read_forces_dat && !reading_forces) read_all_forces();
-    InteratomicForce** retval = new InteratomicForce*[16];
-    init_nulls(retval, 16);
+    /*InteratomicForce** retval = new InteratomicForce*[16];


Should remove this dead code.

primaryodors · 2023-07-11T17:22:07Z

test/motif_test.pepd

 IF %motif > 0 THEN ECHO "Found PMLNPLIYSLRNKD motif at " %motif

+SEARCH 1 %SEQLENA "XXXXXXXXXX$" %motif
+IF %motif > 0 THEN ECHO "Found KLFNKRISS motif at " %motif


This should just say terminal motif or XXXX$ motif, rather than assuming the sequence.

primaryodors · 2023-07-11T17:23:16Z

test/point_test.approved.txt

@@ -4,7 +4,7 @@ Point pt is not in bounding box [pt1, pt2].
 Point pt3 is in bounding box [pt1, pt2].
 Points pt and pt1 are 90 degrees apart relative to [0,0,0].
 SCoord v from point pt5 has r=3.55809, theta=60.6047, phi=246.371.
-Point pt6 from SCoord v is 3.57628e-07 Angstroms from pt5.
+Point pt6 from SCoord v is 3.52537e-07 Angstroms from pt5.


Can this be rounded down to zero, or else just indicated that it's less than some threshold value?

SCRIPTING.md

primaryodors · 2023-07-11T17:27:46Z

www/receptor.php

@@ -47,6 +47,8 @@
 	"6.40" => "HCMDENQ",
 ];

+$gprots = [ "hGNAL", "hGNAS2", "hGNAQ", "hGNAO1" ];


Would be preferable to make this a dynamic list vs. hard coded.

Feel free to open an issue if this would be more than a quick 15 minute task.

primaryodors · 2023-07-11T17:29:12Z

www/receptor.php

@@ -71,7 +73,52 @@ function load_viewer(obj)
                $("[type=file]", embdd.contentDocument).hide();
                var filediv = $("#filediv", embdd.contentDocument)[0];

+                <?php if (file_exists("../pdbs/coupled/$fam/{$rcpid}_hGNAL.pdb")) { ?>


Shouldn't rely on GNAL being always present; if any G protein coupled model exists, it should trigger the appearance of the dropdown.

primaryodors · 2023-07-11T17:33:06Z

Not wanting to wait for the requested changes on this ticket, the 3 letter fix has been added to stable so that the current stable branch is no longer broken.

primaryodors · 2023-07-11T17:35:20Z

test/unit_test_master.sh

            printf "${RED}TAAR test FAILED: bad contacts.${NC}\n"
        else
-            printf "${GRN}TAAR test succeeded.${NC}\n"
+            if [ -z "$TAARPDB" ]; then
+                printf "${RED}TAAR test FAILED: bad PDB data.${NC}\n"


Let's also add the 3 letter test to the d-limonene test dock.

primaryodors · 2023-07-13T00:33:09Z

PR rejected.

primaryodors and others added 9 commits June 28, 2023 12:49

Fixed an unrelated segfault that was an obstacle.

9b268dd

Fix for #282 before work can be done on #287.

1185db8

Copy multi-protein functionality from couple-pepd.

ce5da8d

Necessary files.

60a48e4

Download file command.

322267e

Coplanar pi hydrogens.

4e1bc22

Download once option.

03b1016

AlphaFold JSON download.

a7de14c

Remove raw PDBs that can be downloaded.

0365893

Julie Gagnon added 4 commits July 4, 2023 20:12

PDBs for download.

3005b9f

...

019f498

When UPRIGHTing, move and rotate all strands as a unit.

b6caeb1

Regions for upright.

9ae79df

Julie Gagnon added 12 commits July 5, 2023 17:40

Pepd code for coupling.

3f95978

Homology fix: target != working.

b877432

Fixes.

f54e927

GNAO1 fix.

d888902

Also, hydrogenate means hydrogenate. Not add a bunch of non-coplanar heavy pi atoms that cause warnings in the program output.

Cronnable couples.

512f26d

Cron fixes.

4f3058a

...

2dd243b

Prediction using all 4 G proteins.

6ffcfdf

Fix unit test.

5b6226e

Merge branch 'ssepeq-coupled-homology' of https://github.com/primaryo…

2b6bec5

…dors/primarydock into ssepeq-coupled-homology

Silly mistake fix.

662b52d

Merge branch 'ssepeq-coupled-homology' of https://github.com/primaryo…

a45d71a

…dors/primarydock into ssepeq-coupled-homology

Case insensitive accuracy.

f4e7126

Julie Gagnon and others added 2 commits July 10, 2023 17:36

Coupled clash avoidance.

abda89e

Decrease van der Waals bond distance.

70a301e

#293

primaryodors mentioned this pull request Jul 11, 2023

vdW bond distance is too large. #293

Closed

electronicsbyjulie marked this pull request as ready for review July 11, 2023 03:21

Julie Gagnon added 5 commits July 10, 2023 20:43

Copy PDB 3letter fix from other branch.

02889e1

Reset vdW distances.

1716f63

Unit test success.

3da996f

Unit test for 3-letter bug.

36a50af

Merge branch 'vdW-bond-distance' into ssepeq-coupled-homology

61839a7

electronicsbyjulie linked an issue Jul 11, 2023 that may be closed by this pull request

vdW bond distance is too large. #293

Closed

primaryodors mentioned this pull request Jul 11, 2023

Look into effect of missing PDB atoms in protein coupling. #294

Closed

primaryodors requested changes Jul 11, 2023

View reviewed changes

This was linked to issues Jul 12, 2023

Hydrogenation is failing to observe coplanar rules. #287

Closed

Pepteditor: Helix function is warping side chains. #282

Open

electronicsbyjulie removed a link to an issue Jul 12, 2023

Pepteditor: Helix function is warping side chains. #282

Open

Julie Gagnon added 5 commits July 11, 2023 22:34

Delete working strand test.

19ea7f2

More requested changes.

21c6e04

Almost time to 🤜⏰

4245d53

Atom::get_geometry_aligned_to_bonds()

bbcc3c7

Merge commit '1185db8' into ssepeq-coupled-homology

ff1787d

primaryodors closed this Jul 13, 2023

primaryodors deleted the ssepeq-coupled-homology branch July 13, 2023 00:33

electronicsbyjulie restored the ssepeq-coupled-homology branch July 13, 2023 00:42

Repository owner deleted a comment from electronicsbyjulie Jul 13, 2023

primaryodors removed a link to an issue Jul 14, 2023

Hydrogenation is failing to observe coplanar rules. #287

Closed

primaryodors deleted the ssepeq-coupled-homology branch September 27, 2023 06:13

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Coupled Homology #290

Coupled Homology #290

electronicsbyjulie commented Jul 4, 2023

electronicsbyjulie commented Jul 5, 2023

electronicsbyjulie commented Jul 5, 2023

primaryodors commented Jul 5, 2023

electronicsbyjulie commented Jul 7, 2023

electronicsbyjulie commented Jul 11, 2023

primaryodors Jul 11, 2023

primaryodors Jul 11, 2023

primaryodors Jul 11, 2023

primaryodors Jul 11, 2023

primaryodors Jul 11, 2023

primaryodors Jul 11, 2023

primaryodors Jul 11, 2023

primaryodors Jul 11, 2023

primaryodors Jul 11, 2023

primaryodors commented Jul 11, 2023

primaryodors Jul 11, 2023

primaryodors commented Jul 13, 2023

Coupled Homology #290

Coupled Homology #290

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electronicsbyjulie commented Jul 4, 2023

electronicsbyjulie commented Jul 5, 2023

electronicsbyjulie commented Jul 5, 2023

primaryodors commented Jul 5, 2023

electronicsbyjulie commented Jul 7, 2023

electronicsbyjulie commented Jul 11, 2023

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primaryodors commented Jul 13, 2023