Calculating the binding free energy of a ligand to a protein receptor is a crucial goal in drug discovery. Molecular mechanics/Generalized-Born (Poisson–Boltzmann) surface area (MM/GB(PB)SA), which balances accuracy and efficiency, is one of the most widely used methods for evaluating ligand binding free energies in virtual screening. Uni-GBSA is an automatic workflow to perform MM/GB(PB)SA calculations. It includes several functions including but not limited to topology preparation, structure optimization, binding free energy calculation, and parameter scanning for MM/GB(PB)SA calculations. It also has a batch mode that allows the evaluation of thousands of molecules against one protein target simultaneously, enabling its application in virtual screening.
To run uni-GBSA, you need to install several third-party softwares including acpype, gmx_MMPBSA, lickit, etc.
conda create -n gbsa -c conda-forge acpype openmpi mpi4py gromacs
conda activate gbsa
pip install unigbsa gmx_MMPBSA>=1.5.6 lickitYou can also build a docker image using this file or pull from the docker hub docker pull dockerymh/unigbsa
FROM continuumio/miniconda3
# 1. create a enverioment
SHELL ["/bin/bash", "-c"]
RUN conda create -n gbsa -c conda-forge acpype openmpi mpi4py gromacs \
&& echo 'conda activate gbsa' >> ~/.bashrc \
&& rm -rf /opt/conda/pkgs/*
# 2. install unigbsa
RUN source ~/.bashrc \
&& pip install unigbsa gmx_MMPBSA>=1.5.6 lickit \
&& rm -rf ~/.cache/*
$ unigbsa-pipeline -h
usage: unigbsa-pipeline [-h] -i RECEPTOR [-l LIGAND [LIGAND ...]] [-c CONFIG] [-d LIGDIR] [-f PBSAFILE] [-o OUTFILE] [-nt THREAD]
[--decomp] [--verbose] [-v]
GBSA Calculation. Version: 0.0.9_dev
options:
-h, --help show this help message and exit
-i RECEPTOR Input protein file with pdb format.
-l LIGAND [LIGAND ...]
Ligand files to calculate binding energy.
-c CONFIG Configue file, default: /opt/miniconda3/envs/test/lib/python3.10/site-packages/unigbsa-0.0.9.dev0-py3.10.egg/unigbsa/data/default.ini
-d LIGDIR Floder contains many ligand files. file format: .mol or .sdf
-f PBSAFILE gmx_MMPBSA input file. default=None
-o OUTFILE Output file.
-nt THREAD Set number of thread to run this program.
--decomp Decompose the free energy. default:False
--verbose Keep all the files.
-v, --version show program's version number and exit$ unigbsa-pipeline -i example/1ceb/1ceb_protein.pdb -l example/1ceb/1ceb_ligand.sdf -o BindingEnergy.csv
10/08/2022 13:46:09 PM - INFO - Build protein topology.
10/08/2022 13:46:10 PM - INFO - Build ligand topology: 1ceb_ligand
1 molecule converted
10/08/2022 13:46:13 PM - INFO - Running energy minimization: 1ceb_ligand
10/08/2022 13:46:14 PM - INFO - Run the MMPB(GB)SA.
10/08/2022 13:46:18 PM - INFO - Clean the results.
================================================================================
Results: Energy.csv Dec.csv
Frames mode detal_G(kcal/mole)
1 gb -20.4421
This packge contains several commands: unigbsa-scan, unigbsa-pipeline, unigbsa-traj, unigbsa-pbc, unigbsa-buildtop, unigbsa-buildsys, unigbsa-md.
Perform an automatic parameter optimization prior to production MM/GB(PB)SA calculations.
usage: unigbsa-scan [-h] [-i RECEPTOR] [-pd PROTDIR] [-l LIGAND [LIGAND ...]] [-ld LIGDIR] -e E -c PARASFILE [-o OUTDIR]
[-nt THREAD] [--verbose]
GBSA Calculation.
optional arguments:
-h, --help show this help message and exit
-i RECEPTOR Input protein file with pdb format.
-pd PROTDIR Floder contains many protein files. file format: .pdb
-l LIGAND [LIGAND ...]
Ligand files to calculate binding energy.
-ld LIGDIR Floder contains many ligand files. file format: .mol or .sdf
-e E Experiment data file.
-c PARASFILE Parameters to scan
-o OUTDIR Output directory.
-nt THREAD Set number of thread to run this program.
--verbose Keep all the files.Example
unigbsa-scan -i example/scan/protein.pdb -ld example/scan/ -e example/scan/ligands.csv -c example/scan/scan.json -o scan-demo -nt 4A simple, automatic pipeline to perform MM/GB(PB)SA calculations. You only need to provide a protein file (in the PDB format) and ligand files (in the MOL or SDF format). This function will perform an energy minimization then calculate the PBSA/GBSA values for the each input ligand.
- If you want perform energy minimization or MD simulation for the complex automatically, use the
unigbsa-pipelinefunction.
usage: unigbsa-pipeline [-h] -i RECEPTOR [-l LIGAND [LIGAND ...]] [-c CONFIG] [-d LIGDIR] [-f PBSAFILE] [-o OUTFILE] [-nt THREAD] [--decomp] [--verbose]
GBSA Calculation.
optional arguments:
-h, --help show this help message and exit
-i RECEPTOR Input protein file with pdb format.
-l LIGAND [LIGAND ...]
Ligand files to calculate binding energy.
-c CONFIG Configue file, default: default.ini
-d LIGDIR Floder contains many ligand files. file format: .mol or .sdf
-f PBSAFILE gmx_MMPBSA input file. default=None
-o OUTFILE Output file.
-nt THREAD Set number of thread to run this program.
--decomp Decompose the free energy. default:False
--verbose Keep all the files.You can change the parameters for the MM/GB(PB)SA calculations by providing a configue file(default.ini).
; parameters for simulation
[simulation]
; input pose process method:
; input - just use input pose to calculation
; em - run a simple energy minimizaion for the input poses
; md - run a md simulation for the input poses
mode = em
; simulation box type: triclinic, cubic, dodecahedron, octahedron
boxtype = triclinic
; Distance between the solute and the simulation box
boxsize = 0.9
; Specify salt concentration (mol/liter). This will add sufficient ions to reach up to the specified concentration
conc = 0.15
; number of md simulation steps
nsteps = 500000
; number of equilibrium simulation(nvt, npt) steps
eqsteps = 50000
; number of structure to save for the md simulation
nframe = 100
; protein forcefield (gromacs engine)
proteinforcefield = amber03
; ligand forcefield (acpype engine)
ligandforcefield = gaff
; ligand charge method: bcc, gas
ligandCharge = bcc
; parameters for PBSA/GBSA calculation, support all the gmx_MMPBSA parameters
[GBSA]
; calculation name
sys_name = GBSA
; calculation mode, Separated by commas. gb,pb,decomposition
modes = gb
; best parameters for PBSA/GBSA calculations obtained from Wang, Ercheng, et al. Chemical reviews 119.16 (2019): 9478-9508.
igb = 2
indi = 4.0
exdi = 80.0
Perform a PBSA/GBSA calculation of a complex from a MD trajectory. Note: you need to prepare a gromacs
index.ndxfile which contains two groups namedRECEPTORandLIGAND.
unigbsa-traj -h
usage: unigbsa-traj [-h] -i INP -p TOP -ndx NDX [-m {gb,pb,pb+gb,gb+pb}] [-t TRAJ] [-indi INDI] [-dec] [-D]
Free energy calcaulated by PBSA method.
optional arguments:
-h, --help show this help message and exit
-i INP A pdb file or a tpr file for the trajectory.
-p TOP Gromacs topol file for the system.
-ndx NDX Gromacs index file, must contain recepror and ligand group.
-m {gb,pb,pb+gb,gb+pb}
Method to calculate: gb, pb, pb+gb. default:gb
-t TRAJ A trajectory file contains many structure frames. File format: xtc, pdb, gro...
-indi INDI External dielectric constant. detault: 1.0
-dec Decompose the energy. default:false
-D DEBUG model, keep all the files.
Topology preparation for a protein receptor and ligand(s) using gromacs.
unigbsa-buildtop -h
usage: unigbsa-buildtop [-h] [-p PROTEIN] [-l LIGAND] [-pf PROTFORCE] [-lf {gaff,gaff2}] [-o OUTDIR] [-c] [-verbose]
Build topology file for input file.
optional arguments:
-h, --help show this help message and exit
-p PROTEIN Protein file or directory to build topology.
-l LIGAND Ligand file or directory to build topology.
-pf PROTFORCE Protein forcefield.
-lf {gaff,gaff2} Ligand forcefiled: gaff or gaff2.
-o OUTDIR A output directory.
-c Combine the protein and ligand topology. Suppport for one protein and more ligands. default:True
-verbose Keep the directory or not.Build a simulation box for a protein-ligand complex.
unigbsa-buildsys -h
usage: unigbsa-buildsys [-h] -p PROTEIN [-l LIGAND] [-pf PROTFORCE] [-lf {gaff,gaff2}] [-bt BOXTYPE] [-box BOX BOX BOX] [-d D] [-conc CONC] [-o OUTDIR]
Build MD simulation for input file.
optional arguments:
-h, --help show this help message and exit
-p PROTEIN Protein file for the simulation.
-l LIGAND Ligand file or directory for the simulation.
-pf PROTFORCE Protein forcefield.
-lf {gaff,gaff2} Ligand forcefiled: gaff or gaff2.
-bt BOXTYPE Simulation box type, default: triclinic
-box BOX BOX BOX Simulation box size.
-d D Distance between the solute and the box.
-conc CONC Specify salt concentration (mol/liter). default=0.15
-o OUTDIR A output directory.Run a MD simulation of a protein-ligand complex.
unigbsa-md -h
usage: unigbsa-md [-h] -p PROTEIN [-l LIGAND] [-pf PROTFORCE] [-lf {gaff,gaff2}] [-bt BOXTYPE] [-box BOX BOX BOX] [-d D] [-conc CONC] [-o OUTDIR] [-nstep NSTEP] [-nframe NFRAME] [-verbose]
Run MD simulation for input file.
optional arguments:
-h, --help show this help message and exit
-p PROTEIN Protein file for the simulation.
-l LIGAND Ligand file or directory for the simulation.
-pf PROTFORCE Protein forcefield.
-lf {gaff,gaff2} Ligand forcefiled: gaff or gaff2.
-bt BOXTYPE Simulation box type, default: triclinic
-box BOX BOX BOX Simulation box size.
-d D Distance between the solute and the box.
-conc CONC Specify salt concentration (mol/liter). default=0.15
-o OUTDIR A output directory.
-nstep NSTEP Simulation steps. default:2500
-nframe NFRAME Number of frame to save for the xtc file. default:100
-verbose Keep all the files in the simulation.Process PBC condition for a MD trajectory.
unigbsa-pbc -h
usage: unigbsa-pbc [-h] -s TPR -f XTC [-o OUT] [-n NDX]
Auto process PBC for gromacs MD trajector.
optional arguments:
-h, --help show this help message and exit
-s TPR TPR file generated from gromacs or coordinate file.
-f XTC Trajector file to process PBC.
-o OUT Result file after processed PBC.
-n NDX Index file contains the center and output group.- Perform a MM/GB(PB)SA calculation on a ligand file with a protein receptor with
unigbsa-pipeline
unigbsa-pipeline -i ./example/2fvy/protein.pdb -l ./example/2fvy/BGC.mol2- Perform a MM/GB(PB)SA calculation of a complex from a MD trajectory with
unigbsa-traj
unigbsa-traj -i example/3f/complex.pdb -p example/3f/complex.top -ndx example/3f/index.ndx -m pb gb -t example/3f/complex.pdb- Build topology for a protein receptor and a ligand using gromacs.
unigbsa-buildtop
unigbsa-buildtop -p example/2fvy/protein.pdb -pf amber99sb -o topol # build gromacs topology for a single protein
unigbsa-buildtop -p example/2fvy/protein.pdb -pf amber99sb -l example/2fvy/BGC.mol2 -lf gaff -o 2fvy_topol -c # build gromacs topology for protein and ligand complex-
Build a simulation system with
unigbsa-buildsys -
Run a MD simulation with
unigbsa-md -
Process the PBC condition of a MD trjectorywith
unigbsa-pbc
Maohua Yang and others, Uni-GBSA: an open-source and web-based automatic workflow to perform MM/GB(PB)SA calculations for virtual screening, Briefings in Bioinformatics, 2023;, bbad218, https://doi.org/10.1093/bib/bbad218.