Ligand parametrization using peleffy

Introduction

The main purpose of peleffy is to build the parameter files for PELE. Basically, PELE requires two files for each non-standard residue found in the system:

• IMPACT template: a file containing the atom types and parameters of the ligand. Its job is to link each atom with the corresponding parameters using PDB atom names. Thus, PDB atom names in the input PDB file must match with the expected PDB atom names in the Impact file. This file intrinsically contains the information about the topology and connectivity of each residue.

• Rotamer library: a file containing the branches that can rotate with respect to a central atomic core. Each branch consists in a set of consecutive rotatable bonds.

Besides, a third file with the Solvent parameters might be required when employing the OBC implicit solvent.

Prerequisites

Peleffy comes with the PELE Platform installation, so make sure you activate the correct python environment before attempting the tutorial, e.g.

conda activate pele_platform

You also might need Schrödinger software (any version or license type), if your ligand is not yet preprocessed.

Input files

You will need a PDB file containing the ligand, make sure it has:

• unique PDB atom names

• correct protonation

• CONECT lines at the end of the file.

To ensure ligand atoms have unique PDB atom names:

• Open your ligand file in Schrödinger

• Select the ligand with a mouse click

• Go to Build and click on Other edits -> Change atom properties

• Select PDB atom name from the drop down list and select Set unique PDB atom names within residues.

If your PDB file is missing the CONECT lines:

• Make sure you did not disable them in the export window of Maestro.

• Check if your bond orders are assigned correctly, they can be adjusted with Protein Preparation Wizard tool.

Command line

The easiest way to parametrize your ligand is through the command line interface:

python -m peleffy.main my_ligand.pdb

If you need to tweak any parameters, you can choose from several command line arguments:

Parameter	Argument	Functionality
-h --help	None	Show help message and exit
-f NAME	string	OpenForceField’s forcefield name. Default is openff_unconstrained-1.2.0.offxml.
-o PATH --output PATH	string	Output path. Default is the current working directory
-r INT	integer	Rotamer library resolution in degrees. Default is 30.
--with_solvent	None	Generate solvent parameters for OBC.
--as_datalocal	None	Output will be saved following PELE’s DataLocal hierarchy.
-c NAME --charge_method NAME	string	The name of the method to use to compute charges, you can choose one from: gasteiger, am1bcc, OPLS.
--charges_from_file PATH	string	The path to the file with charges.
--chain CHAIN	string	Chain ID of the molecule to parameterize.
--include_terminal_rotamers	None	Do not exclude terminal rotamers when building the rotamer library.

Example: Parametrization of ligand contained in my_ligand.pdb file with openff-1.3.0 force field, rotamer resolution of 10 degrees, am1bcc charge calculation method and custom output directory.

python -m peleffy.main my_ligand.pdb -f openff_unconstrained-1.3.0.offxml -o "ligand_params" -r 10 -c am1bcc

API

If you are comfortable with python, you can make use of peleffy’s API to parametrize your ligand. Follow the steps below to get a general idea how it works and for more details, please refer to peleffy documentation.

1. The first step is always initializing a Molecule object, you can do it either from a PDB file or a string of SMILES

from peleffy.topology import Molecule

molecule = Molecule("my_ligand.pdb")  # from a PDB file
molecule = Molecule(smiles='c1ccc2cc3ccccc3cc2c1', hydrogens_are_explicit=False)  # from SMILES

2. Generating rotamer library

# Create a rotamer library
rotamer_library = RotamerLibrary(molecule)
rotamer_library.to_file('LIG.rot.assign')

3. Parametrization and creating the Impact file

1. with OpenFF

from peleffy.forcefield import OpenForceField
from peleffy.topology import Topology
from peleffy.template import Impact

openff = OpenForceField('openff_unconstrained-1.2.0.offxml')
parameters = openff.parameterize(molecule)
topology = Topology(molecule, parameters)
impact = Impact(topology)
impact.to_file('ligz')

2. with OPLS2005

from peleffy.forcefield import OpenForceField
from peleffy.topology import Topology
from peleffy.template import Impact

openff = OpenForceField('openff_unconstrained-1.2.0.offxml')
parameters = openff.parameterize(molecule, charge_method='OPLS2005')
topology = Topology(molecule, parameters)

impact = Impact(topology)
impact.to_file('ligz')

4. Generating solvent parameters

1. with OpenFF

from peleffy.solvent import OBC2

solvent = OBC2(topology)  # use previously generated topology
solvent.to_file('ligandParams.txt')

2. with OPLS2005

from peleffy.solvent import OPLSOBC

solvent = OPLSOBC(topology)  # use previously generated topology
solvent.to_file('solventParamsHCTOBC.txt')

Templates usage

Once the templates have been generated, they can be used in a PELE simulation. PELE will need these templates for any non standard residue included in the system to simulate. It is important to mention that PDB atom names of each non standard residue in the system must match with those names from the structures employed in the template generation. A good practice is to assign unique PDB atom names to non standard residues present in the system, isolate them and, one by one, generate their templates with peleffy. In this way, the system that will be simulated will already contain non standard residues with the right PDB atom names.

Templates must be saved in specific locations so PELE can find them. Each type of template must be saved in a different folder inside the DataLocal directory. DataLocal must be created in the working directory where the simulation runs.

Template	Filename	Directory
OPLS2005 parameters template	ligz, resz, xxxz	DataLocal/Templates/OPLS2005/HeteroAtoms/
OpenFF parameters template	ligz, resz, xxxz	DataLocal/Templates/OpenFF/Parsley/
Rotamer library	LIG.rot.assign, RES.rot.assign, XXX.rot.assign	DataLocal/LigandRotamerLibs/
OBC solvent template (OPLS2005)	ligandParams.txt	DataLocal/OBC/
OBC solvent template (OpenFF)	solventParamsHCTOBC.txt	DataLocal/OBC/