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CHARMM and MM(PB/GB)SA

PB model is recommended when working with CHARMMff files. Nevertheless, the combination of PB/GB models with radii optimized for amber atom types (i.e. bondi, mbondi, mbondi2, mbondi3) and CHARMM force field hasn't been tested extensively. Please, check this thread for more information and proceed with caution.

in gmx_MMPBSA v1.5.x series!!!

In gmx_MMPBSA v1.5.0 we have added a new PB radii set named charmm_radii. This radii set should be used only with systems prepared with CHARMM force fields. The atomic radii set for Poisson-Boltzmann calculations has been derived from average solvent electrostatic charge distribution with explicit solvent. The accuracy has been tested with free energy perturbation with explicit solvent ref.. Most of the values were taken from a *radii.str file used in PBEQ Solver in charmm-gui.

Protein-ligand with LPH atoms BFE calculations (Single Trajectory method) -- CHARMMff files

Info

This example can be found in the examples/Protein_ligand_LPH_atoms_CHARMMff directory in the repository folder

LPH is a positively charged virtual particle attached to halogen atoms. This strategy aims to get a better representation of the halogen bond which is a highly directional, non-covalent interaction between a halogen atom and another electronegative atom (See here for more info). Unfortunately, including these particles in the topology will cause gmx_MMPBSA to end in an error. However, there is a way to generate the files without these particles and get gmx_MMPBSA up and running.

Keep in mind

As the LPH particle is not considered during the calculations in gmx_MMPBSA, take the results with a grain of salt, especially when working with systems where the halogen bond is determinant for the binding.

in gmx_MMPBSA v1.5.x series!!!

We have included standard radii for halogens in charmm_radii set:

  • Cl: 1.86
  • Br: 1.98
  • I: 2.24

This radii set should be used with the following PBSA setup:

Sample input file for PB calculation with halogenated compounds

&general
sys_name="PB_Halogens",
PBRadii=7,
/
&pb
inp=1, saopt=1, radiopt=0, cavity_surften=0.005, cavity_offset=0.0000
/

Requirements

In this case, gmx_MMPBSA requires:

Input File required Required Type Description
Input parameters file in input file containing all the specifications regarding the type of calculation that is going to be performed
The MD Structure+mass(db) file tpr pdb Structure file containing the system coordinates
Receptor and ligand group integers Receptor and ligand group numbers in the index file
A trajectory file xtc pdb trr final GROMACS MD trajectory, fitted and with no pbc.
A topology file top take into account that *.itp files belonging to the topology file should be also present in the folder
A Reference Structure file pdb Complex reference structure file (without hydrogens) with the desired assignment of chain ID and residue numbers

-> Must be defined -- -> Optional, but recommended -- -> Optional

See a detailed list of all the flags in gmx_MMPBSA command line here

In order to generate the corresponding files (The MD Structure+mass(db), index, trajectory and the topology files) without the LPH particles, it's necessary to run a few commands. Bear with me!

Let's generate the index file first:

Important

The main idea here is to generate a receptor group, a ligand group without the LPH particles and a complex group containing both the receptor and the ligand without the LPH particles. In general, index files generated with GROMACS directly will contain more detailed information (i.e., receptor and ligand separated)

gmx make_ndx -f com.tpr -o index_mod_gromacs.ndx

  0 System              : 70483 atoms
  1 Protein             :  5580 atoms
  2 Protein-H           :  2817 atoms
  3 C-alpha             :   334 atoms
  4 Backbone            :  1002 atoms
  5 MainChain           :  1335 atoms
  6 MainChain+Cb        :  1654 atoms
  7 MainChain+H         :  1654 atoms
  8 SideChain           :  3926 atoms
  9 SideChain-H         :  1482 atoms
 10 Prot-Masses         :  5580 atoms
 11 non-Protein         : 64903 atoms
 12 Other               : 64903 atoms
 13 3G5                 :    32 atoms
 14 CLA                 :    62 atoms
 15 SOD                 :    63 atoms
 16 TIP3                : 64746 atoms

Splitting the ligand (group 13) by atoms
>splitat 13

Grouping both LPH particles
>47|48

Excluding both LPH particles from the ligand
>13&!49

Naming ligand as lig
>name 50 lig

Grouping rec and lig
>1|50

Cleaning
>del 17-49

save and quit
>q

This is how it should look like at the end

  0 System              : 70483 atoms
  1 Protein             :  5580 atoms
  2 Protein-H           :  2817 atoms
  3 C-alpha             :   334 atoms
  4 Backbone            :  1002 atoms
  5 MainChain           :  1335 atoms
  6 MainChain+Cb        :  1654 atoms
  7 MainChain+H         :  1654 atoms
  8 SideChain           :  3926 atoms
  9 SideChain-H         :  1482 atoms
 10 Prot-Masses         :  5580 atoms
 11 non-Protein         : 64903 atoms
 12 Other               : 64903 atoms
 13 3G5                 :    32 atoms
 14 CLA                 :    62 atoms
 15 SOD                 :    63 atoms
 16 TIP3                : 64746 atoms
 17 lig                 :    30 atoms
 18 Protein_lig         :  5610 atoms

Note

Note that the number of atoms in the generated complex is 5610 because it doesn't include the LPH particles.

Let's generate the MD Structure+mass(db) file:

echo 18 | gmx trjconv -s com.tpr -f traj_fit.xtc -dump 0 -o str_noLP.pdb -n index_mod_gromacs.ndx

Open str_noLP.pdb in your favorite visualizer and see it doesn't contain the LPH particles. Now, let's generate the trajectory with no LPH particles:

echo 18 | gmx trjconv -s com.tpr -f traj_fit.xtc -o com_traj.xtc -n index_mod_gromacs.ndx

Finally, let's edit the topology file. Go inside the toppar folder and open the HETA.itp file. As you will see, we deleted all the information related with LPH particles (atom numbers 31, and 32 respectively). In this case, we deleted the information for LPH particles in atoms (lines 47, 48) and pairs (lines 124, 132, 150, 153, 154, 157, 158, 159). Besides, delete the whole [ virtual_sites3 ] (lines 296-299) and [ exclusions ] (lines 301-318) fields. The original .itp (HETA_original_with_LPH_info.itp) is included for comparison purposes.

Command-line

That being said, once you are in the folder containing all files, the command-line will be as follows:

gmx_MMPBSA -O -i mmpbsa.in -cs str_noLP.pdb -ci index_mod_gromacs.ndx -cg 1 17 -ct com_traj.xtc -cp topol.top -o FINAL_RESULTS_MMPBSA.dat -eo FINAL_RESULTS_MMPBSA.csv
mpirun -np 2 gmx_MMPBSA MPI -O -i mmpbsa.in -cs str_noLP.pdb -ci index_mod_gromacs.ndx -cg 1 17 -ct com_traj.xtc -cp topol.top -o FINAL_RESULTS_MMPBSA.dat -eo FINAL_RESULTS_MMPBSA.csv

where the mmpbsa.in input file, is a text file containing the following lines:

Sample input file for PB calculation
Sample input file for PB calculation
This input file is meant to show only that gmx_MMPBSA works. Althought,
we tried to used the input files as recommended in the Amber manual,
some parameters have been changed to perform more expensive calculations
in a reasonable amount of time. Feel free to change the parameters 
according to what is better for your system.

&general
sys_name="Prot-Lig-ST",
startframe=5,
endframe=9,
solvated_trajectory=0,
# In gmx_MMPBSA v1.5.0 we have added a new PB radii set named charmm_radii. 
# This radii set should be used only with systems prepared with CHARMM force fields. 
# Uncomment the line below to use charmm_radii set
#PBRadii=7,
/
&pb
# radiopt=0 is recommended which means using radii from the prmtop file
# for both the PB calculation and for the NP calculation

istrng=0.15, fillratio=4, radiopt=0, inp=1,
/

Remember

radiopt = 0 is recommended which means using radii from the prmtop file

See a detailed list of all the options in gmx_MMPBSA input file here as well as several examples

Considerations

In this case, a single trajectory (ST) approximation is followed, which means the receptor and ligand structures and trajectories will be obtained from that of the complex. To do so, an MD Structure+mass(db) file (str_noLP.pdb), an index file (index_mod_gromacs.ndx), a trajectory file (com_traj.xtc), and both the receptor and ligand group numbers in the index file (1 17) are needed. The mmpbsa.in input file will contain all the parameters needed for the MM/PB(GB)SA calculation. A topology file is also needed (mandatory) in this case to generate the topology files in amber format with all the terms for CHARMM force field.

A plain text output file with all the statistics (default: FINAL_RESULTS_MMPBSA.dat) and a CSV-format output file containing all energy terms for every frame in every calculation will be saved. The file name in '-eo' flag will be forced to end in [.csv] (FINAL_RESULTS_MMPBSA.csv in this case). This file is only written when specified on the command-line.

Note

Once the calculation is done, the results can be analyzed in gmx_MMPBSA_ana (if -nogui flag was not used in the command-line). Please, check the gmx_MMPBSA_ana section for more information


Last update: June 10, 2022 22:08:08
Created: October 17, 2020 22:35:03
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