Ligand Parameterization Terminology

Overview of Ligand Parameterization and Terminology

In most tutorials for the Amber Molecular Dynamics package, the first stage of that tutorial is running a ligand parameterization to determine the force field parameters for the ligand.

This is usually done as a multi-stage process, that usually involves some combination of the following steps:

  • Ligand Cleaning (by hand/script)

  • Atom Type Assignment with (Antechamber)

  • Initial BCC or ABCG2 Charge Assignment (Antechamber)

  • Electronic Structure Theory Geometry Optimization and RESP Charge Calculation (Gaussian)

  • RESP Charge Fitting (resp.F)

  • Charge Equalization (By hand/script)

  • Assignment of Bonded/Angle/Dihedral Parameters (Parmchk2)

  • Writing a lib file (tleap)

  • PDB Name Matching (By hand/script)

In a wide-range of scenarios, some or most of these steps are omitted in tutorials to streamline the parameterization process. This can lead to the scenario that tutorials are teaching methods that groups are not actually using to develop force-field parameters for ligands in reality. In the following section, we will outline the use of LigandParam, a software tool developed by the York group for making Ligand Parameterization easy to do in a way that matches our best practices.

With that said, before we show you the tool, there are a few important concepts that should be defined.

1. Atom Types: Atom types are the building blocks used by amber force-fields to assign interaction parameters within a molecule. These are usually specific to both chemical element and bonding environment. An sp3 carbon will get different parameters than an sp2 carbon, and so forth.

1. Charge Models: An important part of the force-field parameterization process is the assignment of partial atomic charges to the atoms in the ligand. These charges are used to describe the electrostatic interactions between atoms. There are a variety of charge models that can be used, including:

  • RESP (Restrained Electrostatic Potential) Fitting

  • AM1-BCC

  • ABCG2

The original (and often widely used) charge model is AM1-BCC - this is likely the one you will find in most tutorials. AMBER recently created a new charge model, called ABCG2, which has been shown to lead to improvements in things like solvation free energies. Lastly, RESP charges can be calculated from electronic structure theory calculations which provides the most accurate charges but at the highest-expense.

3. PDB Name Matching: This step involves ensuring that the atom names in the ligand’s PDB file match the atom names in the generated force-field files.This is necessary for making sure that the right atoms get the right parameters.