Uni-GBSA: An Automatic Workflow to Perform MM/GB(PB)SA Calculations for Virtual Screening

[Briefings in Bioinformatics]

Background

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. Additionally, it has a batch mode that allows the evaluation of thousands of molecules against one protein target simultaneously, enabling its application in virtual screening.

Install

Install via Conda

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 "gmx_mmpbsa>=1.5.6"
conda activate gbsa
pip install unigbsa lickit

Install by docker images

You can also build a docker image using this file or pull from the docker hub docker pull dockerymh/unigbsa

FROM continuumio/miniconda3

# 1. create an environment
SHELL ["/bin/bash", "-c"]
RUN conda create -n gbsa -c conda-forge acpype openmpi mpi4py gromacs "gmx_MMPBSA>=1.5.6" \
&&  echo 'conda activate gbsa' >> ~/.bashrc \
&&  rm -rf /opt/conda/pkgs/* 

# 2. install unigbsa
RUN source ~/.bashrc \ 
&&  pip install unigbsa lickit \
&&  rm -rf ~/.cache/*

Usage & Example

Usage

$ unigbsa-pipeline -h
usage: unigbsa-pipeline [-h] -i RECEPTOR [-l LIGAND [LIGAND ...]] [-c CONFIG] [-d LIGDIR] [-f PBSAFILE] [-o OUTFILE] [-validate] [-nt THREADS] [--decomp] [--verbose] [-v]

MM/GB(PB)SA Calculation. Version: 0.1.6

optional arguments:
  -h, --help            show this help message and exit
  -i RECEPTOR           Input protein file in pdb format.
  -l LIGAND [LIGAND ...]
                        Ligand files to calculate binding energy for.
  -c CONFIG             Config file, default: /home/jochem/miniforge3/envs/gbsa_test/lib/python3.9/site-packages/unigbsa/data/default.ini
  -d LIGDIR             Directory containing many ligand files. file format: .mol or .sdf
  -f PBSAFILE           gmx_MMPBSA input file. default=None
  -o OUTFILE            Output file.
  -validate             Validate the ligand file. default: False
  -nt THREADS            Set number of threads 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

Example

$ unigbsa-pipeline -i example/1ceb/1ceb_protein.pdb -l example/1ceb/1ceb_ligand.sdf -o BindingEnergy.csv

07/07/2024 15:56:01 PM - INFO - Build protein topology.
07/07/2024 15:56:02 PM - INFO - Build ligand topology: 1ceb_ligand
07/07/2024 15:56:03 PM - INFO - Running energy minimization: 1ceb_ligand
07/07/2024 15:56:04 PM - INFO - Run the MMPB(GB)SA.
07/07/2024 15:56:12 PM - INFO - Clean the results.
================================================================================
Results: Energy.csv Dec.csv
Frames    mode    delta_G(kcal/mole)
     1      gb              -20.1781  

Other Tools

This packge contains several commands: unigbsa-scan, unigbsa-pipeline, unigbsa-traj, unigbsa-pbc, unigbsa-buildtop, unigbsa-buildsys, unigbsa-md.

unigbsa-scan

Perform an automatic parameter optimization prior to production MM/GB(PB)SA calculations.

$ unigbsa-scan -h
usage: unigbsa-scan [-h] [-i RECEPTOR] [-pd PROTDIR] [-l LIGAND [LIGAND ...]] [-ld LIGDIR] -e E -c PARASFILE [-o OUTDIR] [-nt THREADS] [--verbose]

Perform an automatic parameter optimization prior to production MM/GB(PB)SA calculations.

optional arguments:
  -h, --help            show this help message and exit
  -i RECEPTOR           Input protein file in pdb format.
  -pd PROTDIR           Directory containing many protein files. file format: .pdb
  -l LIGAND [LIGAND ...]
                        Ligand files to calculate binding energy.
  -ld LIGDIR            Directory containing many ligand files. file format: .mol or .sdf
  -e E                  Experiment data file.
  -c PARASFILE          Parameters to scan
  -o OUTDIR             Output directory.
  -nt THREADS            Set number of threads 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 4

unigbsa-pipeline

A 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-pipeline function.

$ unigbsa-pipeline -h
usage: unigbsa-pipeline [-h] -i RECEPTOR [-l LIGAND [LIGAND ...]] [-c CONFIG] [-d LIGDIR] [-f PBSAFILE] [-o OUTFILE] [-validate] [-nt THREADS] [--decomp] [--verbose] [-v]

MM/GB(PB)SA Calculation. Version: 0.1.6

optional arguments:
  -h, --help            show this help message and exit
  -i RECEPTOR           Input protein file in pdb format.
  -l LIGAND [LIGAND ...]
                        Ligand files to calculate binding energy for.
  -c CONFIG             Config file, default: default.ini
  -d LIGDIR             Directory containing many ligand files. file format: .mol or .sdf
  -f PBSAFILE           gmx_MMPBSA input file. default=None
  -o OUTFILE            Output file.
  -validate             Validate the ligand file. default: False
  -nt THREADS            Set number of threads 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

You can change the parameters for the MM/GB(PB)SA calculations by providing a config 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

unigbsa-traj

Perform a PBSA/GBSA calculation of a complex from a MD trajectory. Note: you need to prepare a gromacs index.ndx file which contains two groups named RECEPTOR and LIGAND.

$ unigbsa-traj -h
usage: unigbsa-traj [-h] -i INP -p TOP -ndx NDX [-m MODE [MODE ...]] [-f MMPBSAFILE] [-t TRAJ] [-nt THREADS] [-D] [-v]

Free energy calcaulation by MM/GB(PB)SA 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 receptor and ligand group.
  -m MODE [MODE ...]  MM/GB(PB)SA mode
  -f MMPBSAFILE       Input MM/GB(PB)SA file
  -t TRAJ             A trajectory file containing many structure frames. File format: xtc, pdb, gro...
  -nt THREADS          Set number of threads to run this program.
  -D                  DEBUG model, keep all the files.
  -v, --version       show program's version number and exit

unigbsa-buildtop

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] [-nt THREADS] [-verbose] [-v]

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 forcefield: gaff or gaff2.
  -o OUTDIR         The output directory.
  -c                Combine the protein and ligand topology. Suppport for one protein and more ligands. default:True
  -nt THREADS        Number of threads to run this simulation.
  -verbose          Keep the directory or not.
  -v, --version     show program's version number and exit

unigbsa-buildsys

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] [-nt THREADS] [-v]

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 forcefield: 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         The output directory.
  -nt THREADS        Number of threads to run this simulation.
  -v, --version     show program's version number and exit

unigbsa-md

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] [-nsteps NSTEP] [-nframe NFRAME]
                  [-nt THREADS] [-verbose] [-v]

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 forcefield: 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         The output directory.
  -nsteps NSTEP     Simulation steps. default:2500
  -nframe NFRAME    Number of frames to save for the xtc file. default:100
  -nt THREADS        Number of threads to run this simulation.
  -verbose          Keep all the files in the simulation.
  -v, --version     show program's version number and exit

unigbsa-pbc

Process PBC condition for a MD trajectory.

$ unigbsa-pbc -h
usage: unigbsa-pbc [-h] -s TPR -f XTC [-o OUT] [-n NDX] [-v]

Auto process PBC for gromacs MD trajectory.

optional arguments:
  -h, --help     show this help message and exit
  -s TPR         TPR file generated from gromacs or coordinate file.
  -f XTC         Trajectory file to process PBC.
  -o OUT         Results file after processed PBC.
  -n NDX         Index file contains the center and output group.
  -v, --version  show program's version number and exit

More Examples

• 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 trajectory with unigbsa-pbc

Citation

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.