Java solutions for cheminformatics
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Java Solutions for Cheminformatics. Conformer generation. June 2006. The “modeling” team at ELTE (Eötvös Loránd University). Ödön Farkas General leadership Geometry optimization Fragment fuse Search involving geometry constraints , etc. Imre Jákli Molecular dynamics (MD)

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Java Solutions for Cheminformatics

Conformer generation

June 2006


The “modeling” team at ELTE (Eötvös Loránd University)

Ödön Farkas

  • General leadership

  • Geometry optimization

  • Fragment fuse

  • Search involving geometry constraints, etc.

    Imre Jákli

  • Molecular dynamics (MD)

  • Database connection

    Adrián Kalászi

  • Molecular mechanics

  • Drug design tools (3D pharmacophore model)

  • Conformer search via MD

    Gábor Imre

  • 3D builder scheduling

  • Fragment-atom fuse (v2)

  • Minkowski-based build

  • Debug tools

    Students: Krisztina Szölgyén, László Antall


Conformer generation / basic concepts

  • Conformers are locally stable structures of a molecule.

    • Conformers are often called “rotamers”, however rings may also have different conformers which are not rotamers.

  • Intermediate structures, corresponding to molecular motion, are conformations and should not be considered as conformers.

  • The lowest energy conformer can only be found certainly if all conformers are known.

  • The distribution of conformers can be approximated using the calculated conformational energy.


Goal of conformer generation

  • Generating valid 3D molecular structures

  • Finding multiple structures for flexible molecules


History of conformer generation in Marvin

  • First approach based on a generalized Minkowski metricG. Imre, G. Veress, A. Volford, Ö. Farkas “Molecules from the Minkowski space: an approach to building 3D molecular structures” J. Mol. Struct. (Theochem)666-667, 51 (2003)

  • Due to problems with chirality and slow computational time we introduced an atom-by-atom fuse methodG. Imre, Ö. Farkas“3D Structure Prediction and Conformational Analysis” 7th ICCS, June 5 - 9, 2005 Noordwijkerhout, The Netherlands

    • Scheduling is important

    • Faster and reliable process

    • Frequent use of geometry optimization may slow down the process

  • Current version is based on fusing fragments


Key algorithms used or developed for conformer generation

  • Quaternion fit (JQuatFit)

  • Based on the work of Hamilton

  • http://en.wikipedia.org/wiki/Quaternion

  • Can fit two molecular structures via non-iterative, linear scaling, extremely fast method.

  • Used for fitting common atoms for fusing fragments

  • Substructure3DSearch

  • Based on the substructure search implemented by ChemAxon

  • Simplified for fast exact match (using graph invariant)

  • Extended with

    • geometry matching (using quatfit) to separate conformers

    • high/low priority matching for selecting suitable fuse positions

    • geometry constrained topological matching for fragment re-use

  • Can quickly distinguish conformers with optional diversity limit


Conformer tools in the GUI MSketch/MView

Draw a molecule


Conformer tools in the GUI MSketch/MView

Draw a molecule

  • Adjust Clean/3D mode

  • Fast build: old algorithm, no Hydrogens

  • Fine build: new algorithm,automatically adds Hydrogens

  • Build or optimize: build only for non 3D structures

  • Optimize: just optimize

Press Ctrl-3 to process


Conformer tools in the GUI MSketch/MView

Pressing F7 changes for

3D rotation mode to

change the viewpoint

Previously Ctrl-F generated conformers,now it only displays if they are available

The new Conformerplugin is advised for conformer generation


Conformer tools in the GUI MSketch/MView calculator plugins

  • The conformer plugin allows easy access tothe most importantoptions:

  • Output as molecule array or storage in single molecule

  • Variable optimization criteria

  • Multiple or single conformer

  • Maximum conformer count

  • Time limit for the process

  • “Hyperfine” mode for thorough checking of conformers

  • H-bond visualization

  • Access to old algorithm


Conformer tools in the GUI MSketch/MView calculator plugins

  • The conformer plugin allows easy access tothe most importantoptions:

  • Output as molecule array or storage in single molecule

  • Variable optimization criteria

  • Multiple or single conformer

  • Maximum conformer count

  • Time limit for the process

  • “Hyperfine” mode for thorough checking of conformers

  • H-bond visualization

  • Access to old algorithm


Conformer tools in the GUI MSketch/MView calculator plugins

The conformers canalso be stored as aproperty of the molecule(available in mrv, sdf)

  • Single molecule appearsas a result and “Ctrl-F”displays the stored the individual conformers

  • The desired conformer to display can be selected

  • The selected conformershould be confirmed.


Conformer tools in the GUI MSketch/MView calculator plugins

The stored conformersthen will appear when “Ctrl-F” is pressed.


Molecular dynamics in the GUI MSketch/MView calculator plugins

The stored conformersthen will appear when “Ctrl-F” is pressed.

The flexibility of the

molecule can be studiedvia molecular dynamics.


Molecular dynamics in the GUI MSketch/MView calculator plugins


Command line conformer tools (cxcalc)conformers & leconformers

Usage:

cxcalc [general options] [input files/strings] conformers

[conformers options] [input files/strings]

conformers options:

-h, --help this help message

-f, --format <output format> should be a 3D format (default: sdf)

-m, --maxconformers <maximum number of conformers to be generated>

(default: 100)

-s, --saveconfdesc [true|false] if true a single conformer is saved

with a property containing conformer information

(default: false)

-e, --hyperfine [true|false] if true hyperfine option is set

(default: false)

-o, --oldalg [true|false] if true old (before Marvin 4.1) algorithm

is used for calculation (default: false)

-y, --prehydrogenize [true|false] if true prehydrogenize is done before

calculation, if false calculation is done without

hydrogens (available only with old algorithm,

default: false)

-l, --timelimit <timelimit for calculation in sec> (default: 900)

-O, --optimization [0|1|2|3] conformer generation optimiztaion limit

(default: 1)

# cxcalc conformers -m 250 -s true test.sdf


Command line molecular dynamics tools (cxcalc)moldyn

Usage:

cxcalc [general options] [input files/strings] moldyn

[moldyn options] [input files/strings]

moldyn options:

-h, --help this help message

-x, --forcefield [dreiding] forcefield used for calculation

(default: dreiding)

-i, --integrator [positionverlet|velocityverlet|leapfrog]

integrator type used for calculation

(default: velocityverlet)

-n, --stepno <number of simulation steps> (default: 1000)

-m, --steptime <time between steps in femtoseconds>

(default: 0.1)

-T, --temperature <temperature in Kelvin> (default: 300 K)

-j, --trajectorytype [mol|sdf] type of output

mol: series of mol frames

sdf: series of sdf frames

(default: sdf)

Example:

cxcalc moldyn test.mol


Conformer tools API

// read input molecule

MolImporter mi = newMolImporter("test.mol");

Molecule mol = mi.read();

mi.close();

// create plugin

ConformerPlugin plugin = new ConformerPlugin();

// set target molecule

plugin.setInputMolecule(mol);

// set parameters for calculation

plugin.setMaxNumberOfConformers(400);

plugin.setTimelimit(900);

// run the calculation

plugin.run();

// get results

Molecule[] conformers = plugin.getConformers();

int conformerCount = plugin.getConformerCount();

Molecule m;

for (int i = 0; i < conformerCount; ++i) {

m = conformers[i]; // same as m = plugin.getConformer(i);

// do something with the conformer ...

}

// do something with the results ...


3D structure generation capabilitiesComparison

CorinaMarvin

15.2 s

Much faster…


3D structure generation capabilitiesComparison

CorinaMarvin

5.9 s

Much faster…


3D structure generation capabilitiesComparison

CorinaMarvin

5.1 s

Much faster…


Result statistics NCI 250K database (August, 2000)

  • 1st round

    • Current method with 120 sec. time limit

    • Conversion rate: 99.92% (failed 193 of 250251)

    • Avarage time is 0.65 sec/molecule

  • 2nd round

    • Old method on the 193 previously failing structures

    • Overall conversion rate: 99.994% (failed 13)


Under development what to expect in the near future

  • 100% conversion rate for valid, medium size structures

  • Optional conformer diversity limit

  • Server version

    • Carrying built up fragments for consequent processes

    • Store and use fragment database

  • Further speedup

  • MMFF94 force field


Acknowledgements


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