Difference between revisions of "Developer's Info Goals"

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! style="width:30%" !|Notes
 
! style="width:30%" !|Notes
 
|-
 
|-
−
|Web server || || Open ||
+
|Web server || Steve ||  
 
|-
 
|-
 
|Integrated development pipeline, including IDE and unit tests || Brian, John ||
 
|Integrated development pipeline, including IDE and unit tests || Brian, John ||
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|Create an RNA test set using systems suggested by Al-Hashimi|| Rodger, John ||
 
|Create an RNA test set using systems suggested by Al-Hashimi|| Rodger, John ||
 
|-
 
|-
−
|HMS Islands ||  || John || Use HMS to determine clusters of best overlaid congeneric poses
+
|HMS Islands || John || Use HMS to determine clusters of best overlaid congeneric poses
 
|-
 
|-
−
|Anchor names || || Brock || Output anchor names alongside molecule number when writing out conformers  
+
|Anchor names || Brock || Output anchor names alongside molecule number when writing out conformers  
 
|-
 
|-
 
|}
 
|}
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|- style="background:lightblue"
 
|- style="background:lightblue"
 
! style="width:50%" !|Tasks
 
! style="width:50%" !|Tasks
−
! style="width:10%" !|src
 
 
! style="width:10%" !|Owner
 
! style="width:10%" !|Owner
 
! style="width:30%" !|Notes
 
! style="width:30%" !|Notes
 
|-
 
|-
−
| put in warning flag for missing flex defn type instead of segfaulting || ||  ||
+
| put in warning flag for missing flex defn type instead of segfaulting || ||  
 
|-
 
|-
−
| update torenv in dock6 beta || fraglib_torenv.dat || JDB ||
+
| update torenv in dock6 beta || JDB ||
 
|-
 
|-
−
| Add total conformers samples || || ||  
+
| Add total conformers samples || ||  
 
|-
 
|-
−
| Put minimize = 0 in flex.defn is a depricated feature in manual ||manual ||LEP ||  
+
| Put minimize = 0 in flex.defn is a depricated feature in manual ||LEP ||  
 
|-
 
|-
−
|input checks in the vs protocol scripts to check whether the step before finalized mpi routines || || ||
+
|input checks in the vs protocol scripts to check whether the step before finalized mpi routines || ||
 
|-
 
|-
−
|SYLVIA Score || ||  ||
+
|SYLVIA Score || ||  
 
|-
 
|-
−
|determine which library generation outputs are appended rather than overwritten, and change to overwrite || || ||
+
|determine which library generation outputs are appended rather than overwritten, and change to overwrite || ||
 
|-
 
|-
−
|put in best first clustering option for database filter || || ||
+
|put in best first clustering option for database filter || ||
 
|-
 
|-
−
|Consensus score (within descriptor score)|| || Open ||  
+
|Consensus score (within descriptor score)|| Open ||  
 
|-
 
|-
−
|Clean GNU warnings || ||  ||
+
|Clean GNU warnings  ||  ||  
 
|-
 
|-
−
|Multigrid footprint text file formatting needs adjustment || || LEP ||
+
|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
+
|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
+
|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
+
|Anchor names ||  Brock || Output anchor names alongside molecule number when writing out conformers
 +
|-
 +
|Fuzzy Docking || || examine multiple conformations and take an average based on fuzzy logic
 +
|-
 +
|Gilson's mining minima || || another approach to incorporating multiple minima (double check this)
 
|-
 
|-
 
|}
 
|}
  
 
<br>
 
<br>
−
 
  
 
=DOCK_DN - De Novo Design=
 
=DOCK_DN - De Novo Design=
Line 85: Line 87:
 
! style="width:10%" !|Owner
 
! style="width:10%" !|Owner
 
! style="width:30%" !|Notes
 
! style="width:30%" !|Notes
 +
|-
 +
|Timing for each anchor - why is it the way it is? || Someone || Goal for 6.11?
 +
|-
 +
|Make the verbose output more readable, and include dev verbose || John || Goal for 6.11
 +
|-
 +
|Cleanse GA from the standard denovo file. || John || Goal for 6.11
 +
|-
 +
|Remove all the unnecessary and commented out code || John || Goal for 6.11
 +
|-
 +
|Completed molecules concatenation || || Need to remove/warning/something the concatenation issue
 
|-
 
|-
 
|Fragment frequency selection || John || Currently testing
 
|Fragment frequency selection || John || Currently testing
Line 141: Line 153:
 
|-
 
|-
 
|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. || ||
 
|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. || ||
 +
|-
 +
|Change term storing fragment name to something more meaningful #energy || || the name of the variable is energy
 +
|-
 +
|Chair vs. boat conformations & stereochemistry - only first is picked, and don't account for the rest of the isomers/conformations. Should keep those. || ||
 
|-
 
|-
 
|}
 
|}
  
 
=DOCK_GA - Genetic Algorithm=
 
=DOCK_GA - Genetic Algorithm=
 +
 +
==General To-Do==
 
{| border="1" cellpadding="8" cellspacing="0" style="background:white; text-align:left; width:90%"
 
{| border="1" cellpadding="8" cellspacing="0" style="background:white; text-align:left; width:90%"
 
|- style="background:lightblue"
 
|- style="background:lightblue"
−
! style="width:75%" !|Tasks
+
! style="width:50%" !|Tasks
−
! style="width:25%" !|src
+
! style="width:10%" !|Owner
−
! style="width:13%" !|Owner
+
! style="width:30%" !|Notes
−
! style="width:10%" !|Complete?
+
|-
 +
|Adaptive maintenance of ensemble based on convergence (extinction, delta max, etc.). || BTB ||
 +
|-
 +
|Add leading 0's to xover output filenames || JDB ||
 +
|-
 +
|DNM replacement unable to build list? || JDB ||
 +
|-
 +
|Multi-layer replacement for Amides || JDB ||
 +
|-
 +
|Compute delta slope of fitness score || BTB ||
 +
|-
 +
|slow down molecular evolution so there are less drastic changes between each successive generation - "delta max/max change" || BTB ||
 +
|-
 +
|bring in new parents (e.g. from a pool of molecules) based on convergence - "migration" || BTB ||
 +
|-
 +
|user defined point vs on-the-fly convergence || BTB ||
 +
|-
 +
|metropolis selection for tournament/roulette || BTB  ||
 
|-
 
|-
−
|Horizontal pruning issue not catching chemically identical molecules || LEP || no
+
|tanimoto coefficient percent change - might be inaccurate due to tan coef behavior || ||  
 
|-
 
|-
−
|Fix bug that collapsed atom coordinates  || everywhere? nowhere? somewhere. || LEP || YES MUAHAHAHAHA!
+
|Rotatable bond changes (???) || || Still unsure what this means - JDB
 
|-
 
|-
−
|Added Delimeter header ||conf_gen_ga || LEP || Yes
+
|Limit number of aromatic rings.|| ||
 
|-
 
|-
−
|Fix xover only feature ||conf_gen_ga || LEP || Yes
+
|Adaptively keep differing #'s of parents and children based on some internal criteria (similarity?) || ||  
 
|-
 
|-
−
|Put in error messages for mut_rate > 1 || conf_gen_ga ||LEP || Yes
+
|Determine whether the dummy vdw file is necessary for all DN (including GA) or just DN. || ||  
 
|-
 
|-
−
|Manual user-defined mutation type ||conf_gen_ga || LEP || Yes
+
|Change term storing mutation name to something more meaningful #energy || || the name of the variable is energy
 
|-
 
|-
−
|Remove check only option || conf_gen_ga || LEP || Yes
+
|}
 +
<br>
 +
 
 +
==Mutations==
 +
{| border="1" cellpadding="8" cellspacing="0" style="background:white; text-align:left; width:90%"
 +
|- style="background:lightblue"
 +
! style="width:50%" !|Tasks
 +
! style="width:10%" !|Owner
 +
! style="width:30%" !|Notes
 
|-
 
|-
−
|Add single molecule evolution in testcase in install dir. || install/test/genetic || LEP ||yes
+
|Adaptive mutation rate || Brock || Change rate of mutation based on some internal criteria
 
|-
 
|-
−
|Add leading 0's to xover output filenames || conf_gen_ga.cpp || JDB || no
+
|Pick location of mutation based on some internal criteria || ||  
 
|-
 
|-
−
|DNM replacement unable to build list? || conf_gen_ga.cpp || JDB || no
+
|Pick mutation type based on ensemble behavior.|| ||  
 
|-
 
|-
−
|Multi-layer replacement for Amides || conf_gen_ga.cpp || JDB || no
+
|If molecules are too large, boost deletion (useful for elitism).|| ||  
 
|-
 
|-
−
|Compute delta slope of fitness score || congen_ga.cpp || BTB ||no
+
|If molecules are too small, boost additive mutations. || ||  
 
|-
 
|-
−
| slow down molecular evolution so there are less drastic canges between each successive generation || congen_ga.cpp || BTB ||no
+
|If molecules are too similar, boost replacements and substitutions. || ||  
 
|-
 
|-
−
| bring in new parents (e.g. from a pool of molecules) based on convergence || confgen_ga.cpp || BTB || no
+
|Mutation type selection based on probability vs. ensemble || ||  
 
|-
 
|-
−
| user defined point vs on-the-fly convergence || confgen_ga.cpp || BTB || no
+
|Change chance of performing a mutation type based on number already tried || || Higher success = lower attempts, Lower success = more attempts, etc.
 
|-
 
|-
−
| metropolis selection for tournament/roulette || conf_gen_ga.cpp || BTB  || no
+
|2 layer replacements || ||  
 
|-
 
|-
 +
|Multilayer substitutions || || Could be kinda difficult or may not even work
 +
|-
 
|}
 
|}
 
<br>
 
<br>
  
 +
==Crossover==
 +
{| border="1" cellpadding="8" cellspacing="0" style="background:white; text-align:left; width:90%"
 +
|- style="background:lightblue"
 +
! style="width:50%" !|Tasks
 +
! style="width:10%" !|Owner
 +
! style="width:30%" !|Notes
 +
|-
 +
|Crossover on multiple points simultaneously, rather than just 1 || ||
 +
|-
 +
|Nonexhaustive crossover - pick subset based on probability || ||
 +
|-
 +
|Nonexhaustive crossover for each pair of parents || || Try a specific number of bonds rather than exhaustively sampling all of them.
 +
|-
 +
|Guided crossover based on score || || Good v Good, Bad v Good, Bad v Bad
 +
|-
 +
|Choose crossover pairs based on measure of similarity (boost crossovers between dissimilar molecules). || ||
 +
|}
 +
<br>
  
−
==To Do List==
+
==Fitness/Pruning/Diversity/Other==
−
# tanimoto coefficient percent change - might be inaccurate due to tan coef behavior
+
{| border="1" cellpadding="8" cellspacing="0" style="background:white; text-align:left; width:90%"
−
# Rotatable bond changes (???)
+
|- style="background:lightblue"
−
# Limit number of aromatic rings.
+
! style="width:50%" !|Tasks
−
#-xover (guided based on score) - Good v Good ; Bad v Good ; Bad v Bad THIS
+
! style="width:10%" !|Owner
−
#Nonexhaustive xover (pick subset of xover based on probability)
+
! style="width:30%" !|Notes
−
#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+).
+
|Turn on and off niching adaptive/extinction || Brock ||
−
#Adaptive maintenance of ensemble based on convergence (extinction, delta max, etc.).
+
|-
−
#Stop convergence.
+
|Reduce boost of fragments and all poor mols with niching || ||
−
#Mutations-
+
|-
−
##Adaptive mutation rate - change rate of mutation based on some internal criteria.
+
|Pareto/multiobjective ga || ||
−
##Pick location of mutation based on some internal criteria.
+
|-
−
##Pick mutation type based on ensemble behavior.
+
|best first pruning - now uses descriptor score even if niching ned to delta to fitness/niching when used|| Brock ||
−
##If molecules are too large, boost deletion (useful for elitism).
+
|-
−
##If molecules are too small, boost additive mutations.
+
|Geometric diversity using Hingarian and Tan pruning || Brock ||
−
##If molecules are too similar, boost replacements and substitutions.
+
|-
−
##mutation type selection based on probability vs ensemble
+
|Horizontal pruning issue not catching chemically identical molecules || LEP ||
−
##Complete x # y mutation so far so less prevalent etc
+
|}
−
##Note: 3 layer substitutions probably aren't going to work.
+
<br>
−
##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 ==
+
== Known Potential Bugs ==
 
#Molecules Processed bug (dock.cpp)
 
#Molecules Processed bug (dock.cpp)
 
#verbose mol stats (amber typer)
 
#verbose mol stats (amber typer)

Latest revision as of 04:31, 30 August 2023

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


DOCK_VS - Virtual Screening/Traditional Docking

Tasks Owner Notes
put in warning flag for missing flex defn type instead of segfaulting
update torenv in dock6 beta JDB
Add total conformers samples
Put minimize = 0 in flex.defn is a depricated feature in 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
Fuzzy Docking examine multiple conformations and take an average based on fuzzy logic
Gilson's mining minima another approach to incorporating multiple minima (double check this)


DOCK_DN - De Novo Design

Current Coding Progress:

Task Owner Notes
Timing for each anchor - why is it the way it is? Someone Goal for 6.11?
Make the verbose output more readable, and include dev verbose John Goal for 6.11
Cleanse GA from the standard denovo file. John Goal for 6.11
Remove all the unnecessary and commented out code John Goal for 6.11
Completed molecules concatenation Need to remove/warning/something the concatenation issue
Fragment frequency selection John Currently testing
Roulette torsion acceptance John Currently testing
Fragment pair selection of fragments matrix method John Currently implementing
Dynamic reference Chris
Addition of 3-mer combination fragment checks John, kinda Post torsion
Adding chirality into internal DOCK fingerprints Brock Would help w/ uniqueness pruning and fragmentation
Uniqueness pruning postprocess John
Uniqueness pruning during growth Brock
MPI integration - each anchor/all anchors Brock
Using RDKit for guided growth - QED, SynthA, etc. Pak, Guilherme Planned for 6.11
When minimizing with descriptor score, make sure fingerprint is turned off xxx
HMS needs to be fixed when no heavy atoms matching.
Add print out anchor with frequency option into fraglib code.
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)
Min and max formal charge. Step down as layers of growth proceed FC = 4 for layers 1-3, FC =3 for 4-5, etc.
Stereo centers / volume overlap pruning
Capping group functions (H, CH3, NH2, NH3, Halogen)
Incorporate GA at the end of each layer (not easy)
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
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.
Change term storing fragment name to something more meaningful #energy the name of the variable is energy
Chair vs. boat conformations & stereochemistry - only first is picked, and don't account for the rest of the isomers/conformations. Should keep those.

DOCK_GA - Genetic Algorithm

General To-Do

Tasks Owner Notes
Adaptive maintenance of ensemble based on convergence (extinction, delta max, etc.). BTB
Add leading 0's to xover output filenames JDB
DNM replacement unable to build list? JDB
Multi-layer replacement for Amides JDB
Compute delta slope of fitness score BTB
slow down molecular evolution so there are less drastic changes between each successive generation - "delta max/max change" BTB
bring in new parents (e.g. from a pool of molecules) based on convergence - "migration" BTB
user defined point vs on-the-fly convergence BTB
metropolis selection for tournament/roulette BTB
tanimoto coefficient percent change - might be inaccurate due to tan coef behavior
Rotatable bond changes (???) Still unsure what this means - JDB
Limit number of aromatic rings.
Adaptively keep differing #'s of parents and children based on some internal criteria (similarity?)
Determine whether the dummy vdw file is necessary for all DN (including GA) or just DN.
Change term storing mutation name to something more meaningful #energy the name of the variable is energy


Mutations

Tasks Owner Notes
Adaptive mutation rate Brock 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
Change chance of performing a mutation type based on number already tried Higher success = lower attempts, Lower success = more attempts, etc.
2 layer replacements
Multilayer substitutions Could be kinda difficult or may not even work


Crossover

Tasks Owner Notes
Crossover on multiple points simultaneously, rather than just 1
Nonexhaustive crossover - pick subset based on probability
Nonexhaustive crossover for each pair of parents Try a specific number of bonds rather than exhaustively sampling all of them.
Guided crossover based on score Good v Good, Bad v Good, Bad v Bad
Choose crossover pairs based on measure of similarity (boost crossovers between dissimilar molecules).


Fitness/Pruning/Diversity/Other

Tasks Owner Notes
Turn on and off niching adaptive/extinction Brock
Reduce boost of fragments and all poor mols with niching
Pareto/multiobjective ga
best first pruning - now uses descriptor score even if niching ned to delta to fitness/niching when used Brock
Geometric diversity using Hingarian and Tan pruning Brock
Horizontal pruning issue not catching chemically identical molecules LEP


Known Potential 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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