About

Overview

The ATB and Repository is intended to facilitate the development of molecular force fields for Molecular Dynamics or Monte Carlo simulations of biomolecular systems. Applications include:

  • The study of biomolecule:ligand complexes
  • Free energy calculations
  • Structure-based drug design
  • The refinement of x-ray crystal complexes

This site provides:

  • A repository for building blocks and interaction parameter files for molecules described using GROMOS force fields.
  • An automated builder to help generate building blocks for novel molecules, compatible with the GROMOS 53A6 force field and in formats appropriate for the GROMACS, GROMOS simulation packages and CNS, Phenix, CCP4 and Refmac5 X-ray refinement packages.
  • Refined geometries for molecules within the repository.
  • Equilibrated starting coordinates for a range of biologically important systems.

Required Input:

  • A coordinate file in Protein Data Bank (PDB) format (including all hydrogen atoms).
  • A connectivity record in PDB format listing all interatomic bonds.
  • The net charge on the molecule.

Output Provided:

  • Building block files (all atom and united atom).
  • Interaction parameter files for the corresponding force field.
  • Optimized geometries (all atom and united atom).

The building block and interaction parameter files are provided in a range of formats that can be used to generate the appropriate topology files.

The ATB Pipeline

The topology builder uses a knowledge-based approach in combination with QM calculations to select parameters consistent with a given force field.

The molecule is initially optimised at the HF/STO-3G (or AM1 or PM3) level then re-optimised at the B3LYP/6-31G* level of theory in implicit solvent (water). The initial charges are estimated by fitting the electrostatic potential using Kollmann-Singh scheme. The Hessian matrix is calculated.

The topology is constructed as follows:

  1. A template building block is generated based on the connectivity records including all possible bonds, angles and dihedral angles.
  2. Atom types and mass types are assigned based on the original PDB file.
  3. An initial list of 1-2 and 1-3 exclusions is generated based on connectivity.
  4. Initial charges are assigned based on QM charges or similarity to known groups.
  5. Charge groups are assigned based on atom connectivity and initial partial charges.
  6. Atoms are reordered based on charge groups.
  7. Bond and angle types are assigned based on (1) atom types, (2) bond lengths or bond angles in the QM optimised geometry and (3) matching force constants derived from the Hessian matrix. Multiple options are listed in ambiguous cases and new types introduced if required.
  8. Redundant proper dihedrals are removed. The multiplicity is determined based on connectivity and substituents. The phase shift is determined by requiring that the optimised lie close to a minimum in the dihedral potential. The force constant is selected based on a combination of atom type and the difference between the QM and classical Hessians. In ambiguous cases multiple options are presented.
  9. Aromatic rings and planar groups are identified based on atom type, connectivity and the optimised geometry.
  10. Improper dihedrals are assigned.
  11. Additional 1-4 exclusions are introduced into aromatic systems.
  12. The charges on atoms in equivalent chemical environments connected by 1, 2, 3, and 4 bonds are averaged.
  13. Any symmetry within the molecules is detected and the charges averaged.
  14. Charge scaling is applied to ensure charges are compatible with the chosen parameter set.
  15. A united atom topology building block is generated from the all atom topology building block by (1) collapsing the charges on the non-polar hydrogen atoms onto the heavy atoms to which they are attached, (2) introducing improper dihedrals to maintain chirality, (3) regenerating exclusion lists and (4) reassigning atoms types as required.
  16. The final files are then converted into a range of formats and the original coordinate files reordered to match that of the building blocks.

Release Notes

Acknowledgements

We would like to acknowledge the many people who have provided feedback during the development phase of this project, in particular, Wilfred van Gunsteren, Philippe Hünenberger, Volker Knecht, Alexandre Bonvin, Bruno Horta, Samuel Genheden and MD group at The University of Queensland, Australia

We would also like to thank Peter Ertl for providing us with the JSME molecular builder.

Useful Links

Software and tools:

  • GROMOS home page.
  • GROMACS home page.
  • Vienna-PTM: A resource for generating protein post-translational modification structures for use in molecular dynamics simulations.
  • PDBeChem: A dictionary of chemical components referred to in PDB entries.
  • Phenix: A software suite for the automated determination of macromolecular structures using X-ray crystallography.
  • CCP4: An integrated suite of programs that allows researchers to determine macromolecular structures by X-ray crystallography.
  • NCI Cactus Server: Online SMILES Translator and Structure File Generator.
  • Open Babel: The Open Source Chemistry Toolbox.
  • JMol and JSMol: JavaScript-Based Molecular Viewers.
  • GAMESS: The General Atomic and Molecular Electronic Structure System.

Related Literature

ATB papers:

  • Malde AK, Zuo L, Breeze M, Stroet M, Poger D, Nair PC, Oostenbrink C, Mark AE.
    An Automated force field Topology Builder (ATB) and repository: version 1.0.
    Journal of Chemical Theory and Computation, 2011, 7(12), 4026-4037.
    DOI: 10.1021/ct200196m
  • Canzar S, El-Kebir M, Pool R, Elbassioni K, Malde AK, Mark AE, Geerke DP, Stougie L, Klau GW.
    Charge Group Partitioning in Biomolecular Simulation.
    Journal of Computational Biology, 2013, 20, 188-198.
    DOI:10.1089/cmb.2012.0239
  • Koziara KB, Stroet M, Malde AK, Mark AE.
    Testing and validation of the Automated Topology Builder (ATB) version 2.0: prediction of hydration free enthalpies.
    Journal of Computer-Aided Molecular Design, 2014, 28, 221-233.
    DOI:10.1007/s10822-014-9713-7

GROMOS papers:

  • Schmid N, Christ CD, Christen M, Eichenberger AP and van Gunsteren WF.
    Architecture, implementation and parallelisation of the GROMOS software for biomolecular simulation.
    Computer Physics Communications, 2012, 183, 890-903.
    DOI:10.1016/j.cpc.2011.12.014
  • Eichenberger AP, Allision JR, Dolenc J, Geerke DP, Horta BAC, Meier K, Oostenbrink C, Schmid N, Steiner D, Wang DQ and van Gunsteren WF.
    GROMOS plus plus Software for the Analysis of Biomolecular Simulation Trajectories.
    Journal of Chemical Theory and Computation, 2011, 7, 3379-3390.
    DOI:10.1021/ct2003622

GROMOS 54A7:

  • Schmid N, Eichenberger AP, Choutko A, Riniker S, Winger M, Mark AE and van Gunsteren WF.
    Definition and testing of the GROMOS force-field versions 54A7 and 54B7.
    European Biophysics Journal, 2011, 40, 843-856.
    DOI: 10.1007/s00249-011-0700-9

GROMOS 53A6:

  • Oostenbrink C, Villa A, Mark AE and van Gunsteren WF.
    A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force-field parameter sets 53A5 and 53A6.
    Journal of Computational Chemistry, 2004, 25, 1656-1676.
    DOI: 10.1002/jcc.20090

GROMOS Lipid Forcefields:

  • Poger D, Mark AE and van Gunsteren WF.
    A new force field for simulating phosphatidylcholine bilayers.
    Journal of Computational Chemistry, 2010, 31, 1117-1125.
    DOI: 10.1002/jcc.21396
  • Poger D and Mark AE.
    On the Validation of Molecular Dynamics Simulations of Saturated and cis-Monounsaturated Phosphatidylcholine Lipid Bilayers: A Comparison with Experiment.
    Journal of Chemical Theory and Computation, 2010, 6, 325-336.
    DOI: 10.1021/ct900487a

GROMOS Sugar Forcefields:

  • Lins RD and Hünenberger PH.
    A new GROMOS force field for Hexopyranose-based carbohydrates.
    Journal of Computational Chemistry, 2005, 26, 1400-1412.
    DOI:10.1002/jcc.20275
  • Hansen HS and Hünenberger PH. A Reoptimized GROMOS Force Field for Hexopyranose-Based Carbohydrates Accounting for the Relative Free Energies of Ring Conformers, Anomers, Epimers, Hydroxymethyl Rotamers, and Glycosidic Linkage Conformers.
    Journal of Computational Chemistry, 2011, 32, 998-1032.
    DOI:10.1002/jcc.21675