Difference between revisions of "Developer's Info Goals"

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=DOCK_GA - Genetic Algorithm=
 
=DOCK_GA - Genetic Algorithm=
 +
{| border="1" cellpadding="8" cellspacing="0" style="background:white; text-align:left; width:90%"
 +
|- style="background:lightblue"
 +
! style="width:75%" !|Tasks
 +
! style="width:25%" !|src
 +
! style="width:13%" !|Owner
 +
! style="width:10%" !|Complete?
 +
|-
 +
|Horizontal pruning issue not catching chemically identical molecules || LEP || no
 +
|-
 +
|Fix bug that collapsed atom coordinates  || everywhere? nowhere? somewhere. || LEP || YES MUAHAHAHAHA!
 +
|-
 +
|Added Delimeter header ||conf_gen_ga || LEP || Yes
 +
|-
 +
|Fix xover only feature ||conf_gen_ga || LEP || Yes
 +
|-
 +
|Put in error messages for mut_rate > 1 || conf_gen_ga ||LEP || Yes
 +
|-
 +
|Manual user-defined mutation type ||conf_gen_ga || LEP || Yes
 +
|-
 +
|Remove check only option || conf_gen_ga || LEP || Yes
 +
|-
 +
|Add single molecule evolution in testcase in install dir. || install/test/genetic || LEP ||yes
 +
|-
 +
|Add leading 0's to xover output filenames || conf_gen_ga.cpp || JDB || no
 +
|-
 +
|DNM replacement unable to build list? || conf_gen_ga.cpp || JDB || no
 +
|-
 +
|Multi-layer replacement for Amides || conf_gen_ga.cpp || JDB || no
 +
|-
 +
|Compute delta slope of fitness score || congen_ga.cpp || BTB ||no
 +
|-
 +
| slow down molecular evolution so there are less drastic canges between each successive generation || congen_ga.cpp || BTB ||no
 +
|-
 +
| bring in new parents (e.g. from a pool of molecules) based on convergence || confgen_ga.cpp || BTB || no
 +
|-
 +
| user defined point vs on-the-fly convergence || confgen_ga.cpp || BTB || no
 +
|-
 +
| metropolis selection for tournament/roulette || conf_gen_ga.cpp || BTB  || no
 +
|-
 +
|}
 +
<br>
 +
 +
 +
==To Do List==
 +
# tanimoto coefficient percent change - might be inaccurate due to tan coef behavior
 +
# Rotatable bond changes (???)
 +
# Limit number of aromatic rings.
 +
#-xover (guided based on score) - Good v Good ; Bad v Good ; Bad v Bad THIS
 +
#Nonexhaustive xover (pick subset of xover based on probability)
 +
#Nonexhaustive xover for each pair of parents - have a set number of bonds for xover rather than trying all of them.
 +
#Crossover on multiple points simultaneously (2-3 crossovers on a given pair to make 3+ children rather than 2+).
 +
#Adaptive maintenance of ensemble based on convergence (extinction, delta max, etc.).
 +
#Stop convergence.
 +
#Mutations-
 +
##Adaptive mutation rate - change rate of mutation based on some internal criteria.
 +
##Pick location of mutation based on some internal criteria.
 +
##Pick mutation type based on ensemble behavior.
 +
##If molecules are too large, boost deletion (useful for elitism).
 +
##If molecules are too small, boost additive mutations.
 +
##If molecules are too similar, boost replacements and substitutions.
 +
##mutation type selection based on probability vs ensemble
 +
##Complete x # y mutation so far so less prevalent etc
 +
##Note: 3 layer substitutions probably aren't going to work.
 +
##2-layer replacements.
 +
#fitness-
 +
##turn on and off niching adaptive/extinction
 +
##reduce boost of fragments and all poor mols with niching
 +
##pareto/mulitobjective ga
 +
#selection-
 +
##Adaptively keep differing #'s of parents and children based on some internal criteria (similarity?)
 +
#extinction-
 +
#which molecules are best-
 +
##best first pruning - now uses descriptor score even if niching ned to delta to fitness/niching when used
 +
## geometric diversity using Hingarian and Tan pruning
 +
#Determine whether the dummy vdw file is necessary for all DN (including GA) or just DN.
 +
#Choose crossover pairs based on measure of similarity (boost crossovers between dissimilar molecules).
 +
 +
== Known Bugs ==
 +
#Molecules Processed bug (dock.cpp)
 +
#verbose mol stats (amber typer)
 +
#molecule being renamed when going into repl even tho it's the same molecule
  
 
=DOCK_CV - Covalent Docking=
 
=DOCK_CV - Covalent Docking=
 +
As of right now only tested on pose reproduction for 2 testcases.
 +
 +
Create a sphere file by using the sidechain of the CYS residue. In this case isolate the sulfur, carbon, and carbon, and save as a pdb. Using the script pdbtosph, convert that pdb to a .sph file to be read by DOCK.
 +
Three atoms are required for spheres and orienting.
 +
 +
Prepare receptor:
 +
Remove the covalently bound ligand. Add Hydrogens and charge to the receptor. Remove the CYS sulfur and the next carbon with their associated Hydrogens only. Save as mol2.
 +
 +
Prepare the ligand:
 +
Remove all of the protein except for the CYS residue. Delete the backbone and some of the sidechain, leaving the sulfur and attached carbon. Add hydrogens and charge, and manually delete the hydrogens added onto the residue sidechain (ie sulfur and carbon). Save ligand as mol2. Open and edit the ligand.mol2 in vi and change the name of the sulfur to D1 and the atomtype to Du. Change the name of the carbon to D2 and the atomtype to Du. Save the ligand mol2.

Revision as of 20:23, 21 October 2022

DOCK 6.11 Information

General DOCK Goals

DOCK_VS - Virtual Screening/Traditional Docking

Tasks src Owner Complete?
put in warning flag for missing flex defn type instead of segfaulting no
update torenv in dock6 beta fraglib_torenv.dat JDB no
Add total conformers samples
Put minimize = 0 in flex.defn is a depricated feature in manual manual LEP no
input checks in the vs protocol scripts to check whether the step before finalized mpi routines no
SYLVIA Score no
determine which library generation outputs are appended rather than overwritten, and change to overwrite no
put in best first clustering option for database filter no
Web server Open No
Consensus score (within descriptor score) Open No
Clean GNU warnings No
Multigrid footprint text file formatting needs adjustment LEP No
Add the DUDE systems created by Jiaye, Brian, and Yuchen to the standard DOCK test set No
Create an RNA test set using systems suggested by Al-Hashimi Rodger, John No
Fix minimization issue with perfectly linear (alkyne) compounds Add dummy atom 90* as in other codes so dihedral is defined, treat the hydrogen as a part of the carbon or heavy atom (united atom) approach, flag dihedrals that are undefined or close to 180* as non rotatable Open No
HMS Islands Use HMS to determine clusters of best overlaid congeneric poses Open No
Anchor names Output anchor names alongside molecule number when writing out conformers Brock No



Tasks src Owner Complete?
verbose ==2 option in dock6 beta utils.cpp LEP yes
Add total conformers samples
Check amide bond rotation during sampling - it's nto a bug it was fixed back in 2014 LEP yes
Write out # of HBond Donors and Acceptors conf_gen_dn, library_file LEP yes
put in compiler directives to compile with or without timespec dock.cpp LEP yes
Fix bug that prints out 2/3 sigfigs instead of 6 for MW and FC library_file, filter, amber_typer LEP Yes
Fix nano/micro/milisecond timer dock.cpp GDRM Yes
ga flag and verbose == 2 for premin_mol in simplex simplex.cpp LEP Yes
Merge Hackathon changes to beta for clean faster code pow/memcpy/mpi pointers everywhere LEP Yes
Add Tip3p atom type to dock vdw.defn fingerprint LEP Yes
Hide secondary scoring function permanently lots LEP Yes
Merge GIST into latest dock grid, master_score, score_descriptor, score_gist LEP Yes
Add second layer of verbosity utils, conf_gen_dn so far LEP Yes
RDKit integration with DOCK GDM Yes
Modify Grid to show error on nonintegrality BTB Yes


DOCK_DN - De Novo Design

This is the Rizzo lab wiki page for coordinating bugs and progress on the de novo project.

Valgrind clean version of the code on cluster that Rizzo lab should be using:

Lauren: 

/gpfs/projects/rizzo/zzz.programs/dock6.9_release
This version includes all changes of the merge.

Path to Generic Fragment Library: 

/gpfs/projects/rizzo/leprentis/gen-frags-12

Path to Frequency Anchors: 

/gpfs/projects/rizzo/leprentis/zinc1_ancs_freq


Current Coding Progress:

Working on these currently:

  1. John: Implement fragment frequency picking as an option
  2. John: Professional web page
  3. John: Implement Adjacency Matrix into fraglib/dn (initialize matrix and utilize matrix for graph and random fragment picking)
  4. Chris: Guided FPS
  5. Lauren: Covalent anchor for denovo growth
  6. Guilherme: rdkit implementation for logp etc



Need to be fixed/added:

  1. methyl and amine capping groups
  2. add print out anchor with frequency option into fraglib code
  3. MPI option for each anchor
  4. aromatic rings
  5. QED
  6. fraglib generation chirality issue
  7. chiral centers
  8. score_molecules and internal_energy problem (for simple_build)
  9. HMS needs to fixed when no heavy atoms matching


Not working on these right now:

  1. Addition of "3mer" combination fragment check (post tors check)
  2. Min and Max formal charge to replace absolute value of charge.(Broke everything) Step down as layers of growth proceed (layers 1-3 FC = 4, Layers 4-5 FC = 3, Layers 6-8 FC = 2)
  3. Capping groups for post growth process (halogens and methyls)
  4. Incorporate tan pruning as final step (post growth) as user option (replace make_unique script) as database filter not dn


Completed:

  1. Lauren: hbond accept/donor descriptor implementation
  2. Chris: increase orienting verbose statistics for dn
  3. John: acceptance based on freq of torsenv
  4. Lauren&John: secondary torenv check of prune dump molecules and testing
  5. Lauren&John: SMILEs and ZINC script (for dn and ga)
  6. Lauren: add dn name with date and counter function
  7. Lauren: Check MGS+(-50)TAN before and after fingerprinting fix for 663 systems
  8. Lauren: determine if random seed is reset for each aps
  9. Lauren: Create testset for each dn function
  10. Lauren: Test simple build function with merged de novo
  11. Lauren&Stephen: clean make_unique script for release
  12. Lauren: merge GA into dock/dn
  13. Dwight & Lauren: MPI wrapper for 192 processors (8 nodes) for testsets on rizzo cluster
  14. Lauren: Create short testsets for denovo frag gen, focused fragment generic for DOCK6.9 release
  15. Dwight+Lauren: merge parameter files of de novo with DOCK
  16. Lauren: add dn_defn file for separate defn with Hydrogens
  17. Lauren: Implement csingleton fix for orienting fragments with less than 3 heavy atoms
  18. Lauren: Test bfochtman fix for rotatable bonds within an user defined anchor
  19. Lauren: Test csingleton fix for orienting fragments with Du
  20. Lauren: Test MGS focused fragment library results with dn paper
  21. Stephen: editting script to calculate SMILE string of de novo molecules in OpenBabel
  22. Stephen: smooth function cutoff for mw
  23. Lauren&John: Rework VS protocol to integrate de novo protocol more smoothly
  24. Lauren&John: Fix torsion problem for prune_dump molecules


List of features that we definitely want for the 6.9 release:

Task Owner Complete?
When minimizing with descriptor score, make sure fingerprint is turned off xxx
Speed up fingerprint calculations by saving reference ligand as a permanent object WJA yep
Add pre-min conformations to growth trees WJA yep
Add verbose flag options WJA yep
Put molecular properties (RB, MW, etc) in mol2 header WJA yep
Put ensemble properties (RB, MW, etc) output stream at the end of each layer WJA yep
Check formal charge prune BCF yep
Combination of horizontal pruning metrics (let's consider dropping tanimoto prune and just using hungarian prune) WJA yep
Finish implementing growth trees WJA yep
Revisit orienting to make sure it is working as intended WJA yep
Fixed a bug where we were marking scaffold_this_layer as true for any fragment WJA yep
Update random sampling function to use last layer changes in graph function WJA yep
Do that same thing for the exhaustive function WJA yep
I don't think we ever clear the scaf_link_sid vector, we definitely should do that somewhere WJA yep
Update exhaustive to combine all frags into one library, just like graph / random. WJA yep


List of features/ideas for future releases:

  • Using different references for different layers of dn growth (GFPS protocol) Guided footprint similarity - divide the reference into smaller pieces (layers) to help guide the growth paths more efficiently (i.e. directed growth)
  • Stereo centers / volume overlap pruning
  • Capping group functions (H, CH3, Halogen)
  • Incorporate GA at the end of each layer (not easy)
  • Overhaul the simple-build function
  • Monte carlo algorithm that checks bond frequency
  • Scaling max root / layer size with layer
  • Select torenv before selecting fragment. Will need to overhaul fraggraph, will keep us from needing to assemble mols that will not pass torenv.
  • Add fragname string to restart and dump files, already done for final and fraglib files.
  • Add ZINC name to torenv table
  • Unusual behavior during library generation when frequency cutoff == 0
  • Print out how many molecules cannot be capped. (Difference between ensemble size and dump.)
  • building from anchor 0 -> building from scf.98
  • Possible torenv check for dump molecules after capping before printing.
  • keep tables of what fragments (and torsion types) are already included in a growing molecule (i.e.e the name string has this info) and only accept a new fragment (or torsion type) within certain ranges and probabilities. In other words use knowledge of chemical makeup probabilities to keep from over including or under including certain fragment and bond types (essentially use datamining to help us only build molecules within certain boundaries)
  • De novo design with scaled VDW parameters. Exaggerate them and ramp them down or vice versus. May help to eliminate the anchor and slop or anchor and slosh problem.


List of SB2012 systems that we will use for tests:

For now, let's use 5-15 rotatable bonds inclusive; total = 709 systems ("drug-like" size molecules). De novo paper only used 663 systems that removed 46 systems where the cognate ligand did not fall with a +/-2 formal charge. (5through15 = 709, 5through15_ch2 = 663)

{5RB = 107; 6RB = 96; 7RB = 103; 8RB = 75; 9RB = 66; 10RB = 75; 11RB = 57; 12RB = 41; 13RB = 38; 14RB = 26; 15RB = 25}


DOCK_GA - Genetic Algorithm

Tasks src Owner Complete?
Horizontal pruning issue not catching chemically identical molecules LEP no
Fix bug that collapsed atom coordinates everywhere? nowhere? somewhere. LEP YES MUAHAHAHAHA!
Added Delimeter header conf_gen_ga LEP Yes
Fix xover only feature conf_gen_ga LEP Yes
Put in error messages for mut_rate > 1 conf_gen_ga LEP Yes
Manual user-defined mutation type conf_gen_ga LEP Yes
Remove check only option conf_gen_ga LEP Yes
Add single molecule evolution in testcase in install dir. install/test/genetic LEP yes
Add leading 0's to xover output filenames conf_gen_ga.cpp JDB no
DNM replacement unable to build list? conf_gen_ga.cpp JDB no
Multi-layer replacement for Amides conf_gen_ga.cpp JDB no
Compute delta slope of fitness score congen_ga.cpp BTB no
slow down molecular evolution so there are less drastic canges between each successive generation congen_ga.cpp BTB no
bring in new parents (e.g. from a pool of molecules) based on convergence confgen_ga.cpp BTB no
user defined point vs on-the-fly convergence confgen_ga.cpp BTB no
metropolis selection for tournament/roulette conf_gen_ga.cpp BTB no



To Do List

  1. tanimoto coefficient percent change - might be inaccurate due to tan coef behavior
  2. Rotatable bond changes (???)
  3. Limit number of aromatic rings.
  4. -xover (guided based on score) - Good v Good ; Bad v Good ; Bad v Bad THIS
  5. Nonexhaustive xover (pick subset of xover based on probability)
  6. Nonexhaustive xover for each pair of parents - have a set number of bonds for xover rather than trying all of them.
  7. Crossover on multiple points simultaneously (2-3 crossovers on a given pair to make 3+ children rather than 2+).
  8. Adaptive maintenance of ensemble based on convergence (extinction, delta max, etc.).
  9. Stop convergence.
  10. Mutations-
    1. Adaptive mutation rate - change rate of mutation based on some internal criteria.
    2. Pick location of mutation based on some internal criteria.
    3. Pick mutation type based on ensemble behavior.
    4. If molecules are too large, boost deletion (useful for elitism).
    5. If molecules are too small, boost additive mutations.
    6. If molecules are too similar, boost replacements and substitutions.
    7. mutation type selection based on probability vs ensemble
    8. Complete x # y mutation so far so less prevalent etc
    9. Note: 3 layer substitutions probably aren't going to work.
    10. 2-layer replacements.
  11. fitness-
    1. turn on and off niching adaptive/extinction
    2. reduce boost of fragments and all poor mols with niching
    3. pareto/mulitobjective ga
  12. selection-
    1. Adaptively keep differing #'s of parents and children based on some internal criteria (similarity?)
  13. extinction-
  14. which molecules are best-
    1. best first pruning - now uses descriptor score even if niching ned to delta to fitness/niching when used
    2. geometric diversity using Hingarian and Tan pruning
  15. Determine whether the dummy vdw file is necessary for all DN (including GA) or just DN.
  16. Choose crossover pairs based on measure of similarity (boost crossovers between dissimilar molecules).

Known Bugs

  1. Molecules Processed bug (dock.cpp)
  2. verbose mol stats (amber typer)
  3. molecule being renamed when going into repl even tho it's the same molecule

DOCK_CV - Covalent Docking

As of right now only tested on pose reproduction for 2 testcases.

Create a sphere file by using the sidechain of the CYS residue. In this case isolate the sulfur, carbon, and carbon, and save as a pdb. Using the script pdbtosph, convert that pdb to a .sph file to be read by DOCK. Three atoms are required for spheres and orienting.

Prepare receptor: Remove the covalently bound ligand. Add Hydrogens and charge to the receptor. Remove the CYS sulfur and the next carbon with their associated Hydrogens only. Save as mol2.

Prepare the ligand: Remove all of the protein except for the CYS residue. Delete the backbone and some of the sidechain, leaving the sulfur and attached carbon. Add hydrogens and charge, and manually delete the hydrogens added onto the residue sidechain (ie sulfur and carbon). Save ligand as mol2. Open and edit the ligand.mol2 in vi and change the name of the sulfur to D1 and the atomtype to Du. Change the name of the carbon to D2 and the atomtype to Du. Save the ligand mol2.

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