Developer's Info Goals

DOCK 6.11 Information

Planned additions:

DOCK 6.10 Information

New features include: an enhanced chemical searching methods termed: molecular evolution DOCK (DOCK_GA), which is an evolution-based method for ligand construction that employs principles of breeding and mutations (see Prentis et al.), a new fragment library generation function was added to the docking protocol, a simplex minimization step ramping functionality for enhanced speed during docking, a new scoring function (internal energy score) that allows for generation and scoring of molecules without a protein, and a molecular weight smoothing function for de novo design that will allow a softer curve of weight distributions in the final ensemble. Secondary score, introduced in 6.1, has been fully removed in this version.

Using this page

This page is designed to be a unified location for development goals we have set for each sampling/experimental type we are able to perform in DOCK. New tasks and goals can be included in the following tables, and can link to their own development pages if need be.

The current page setup includes an Archive page for completed tasks. When a task is deemed complete, please move it to the designated section on the Archive, sign it with your initials, and date it. Any relevant information should also be included in notes, being brief but descriptive (ex. 'pushed addition/fix to GitHub on MM/DD/YYYY, Commit Hash: ######')

If there are any questions on anything for this page, please direct them to any of the current graduate students or post-docs listed on the Contact page. If they don't know an answer to your inquiry, they will be able to direct you to someone that does.

General DOCK Goals

Tasks	src	Owner	Notes
Web server		Open
Integrated development pipeline, including IDE		Brian
Add the DUDE systems created by Jiaye, Brian, and Yuchen to the standard DOCK test set
Create an RNA test set using systems suggested by Al-Hashimi		Rodger, John
HMS Islands	Use HMS to determine clusters of best overlaid congeneric poses	John
Anchor names	Output anchor names alongside molecule number when writing out conformers	Brock

DOCK_VS - Virtual Screening/Traditional Docking

Tasks	src	Owner	Notes
put in warning flag for missing flex defn type instead of segfaulting
update torenv in dock6 beta	fraglib_torenv.dat	JDB
Add total conformers samples
Put minimize = 0 in flex.defn is a depricated feature in manual	manual	LEP
input checks in the vs protocol scripts to check whether the step before finalized mpi routines
SYLVIA Score
determine which library generation outputs are appended rather than overwritten, and change to overwrite
put in best first clustering option for database filter
Consensus score (within descriptor score)		Open
Clean GNU warnings
Multigrid footprint text file formatting needs adjustment		LEP
Fix minimization issue with perfectly linear (alkyne) compounds		Open	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
HMS Islands		Open	Use HMS to determine clusters of best overlaid congeneric poses
Anchor names		Brock	Output anchor names alongside molecule number when writing out conformers

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	Notes
When minimizing with descriptor score, make sure fingerprint is turned off	xxx
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 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.