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Hannes H. Loeffler1, Julien Michel2 and Christopher Woods3
1 STFC Daresbury, Scientific Computing Department, Keckwick Lane, Warrington WA4 4AD, [email protected]
2 School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ3 BrisSynBio, University of Bristol, Beacon House, Queens Road, Bristol BS8 1QU
FESetup: a tool to automate relative alchemical free energy simulation setup
Background:
Free energy methods like Thermodynamic Integration (TI) or Free Energy Perturbation (FEP) can effectively estimate binding affinities of drug–like molecules. Single topology relative alchemical free energy simulations are particularly efficient.
Manual simulation setup is tedious, however, as each ligand must be parameterised, mappings determined, suitable runtime parameters chosen, etc.
To overcome this bottleneck automation is a necessity.
We develop the Python tool FESetup on the basis of the Sire simulation framework and the well–known chemoinformatics toolkits RDKit, Open Babel and antechamber.
The FESetup Tool:
Automatic setup for relative TI and FEP simulations with ligands; MM–PBSA is possible too
Alchemical free energy simulation support for Amber, Gromacs, Sire, CHARMM/PERT
Abstract MD engine for Amber, Gromacs, NAMD, DL POLY
Amber family of force fields, GAFF (AM1/BCC) for ligands
Atoms are automatically mapped using maximum common substructure search (MCSS): similarity defined such that atom or bond types ignored but complete rings only and ring–matches–ring
Linux and OS X builds available: http://www.ccpbiosim.ac.uk/fesetup/
Future Plans:Support for other force fields and simulation packages
Absolute free energies, side–chain mutations, etc
Integration with Lomap2 (David Mobley lab)
Scientific Computing Department
Fig 1: Computation of the free energy of one leg of the relative binding free energy. A second leg of the unbound mutation completes the thermodynamic cycle. FESetup automates the setup and creates topologies and input files for simulation.
Workflow Solution:Make use of existing, well–tested tools and integrate
them into a workflow
Open Babel for file format conversion, energy minimisation, conformation search
RDKit for graph–based mappings (MCSS)
Sire: topology reader and data structures
Antechamber: force field parameterisation for ligands e.g. AM1/BCC
Leap: topology file creation
Fig 2: Workflows in FESetup. Receptor and ligand flows are independent from each other and can be combined into a complex. The morph contains atom mappings and force field parameters.
Goals:Automate what is possible and reasonable
Make setup easier e.g. encode best practices
Robustness of code
Simple usage
topology/coordinates
Ligand
topology/coordinates
Ligand
topology/coordinates
Receptor
Ligand Ligand Receptor
parameterize parameterize protonate
minimisation/MD
minimisation/MD
minimisation/MD
Complex-Morph
Morph Complex
NN
N
N
NSOOAr X
Y
ΔΔG+
NN
N
N
NSOOAr Z
Y
bind
References:● FESetup: DOI 10.1021/acs.jcim.5b00368● Applications: DOIs 10.1021/acs.jpcb,
10.1021/acs.jctc.5b00159, 10.1039/C4CP05572A
