Automation of the CHARMM General Force Field (CGenFF) I: Bond Perception and Atom Typing

TLDR

Molecular mechanics force fields are widely used in drug design, with biomolecular simulations employing specialized force fields for macromolecules and general force fields for drugs, necessitating atom‑type, parameter, and charge assignment for arbitrary drug‑like molecules. The study presents algorithms for bond perception and atom typing in the CHARMM General Force Field (CGenFF). The atom typer assigns attributes such as valence, bond order, and ring membership to atoms and bonds, then uses a programmable decision tree to assign CGenFF atom types. Validated on 477 training and 126 test compounds, the atom typer enables straightforward implementation and updating of CGenFF atom‑typing rules and is available online at https://www.paramchem.org/.

Abstract

Molecular mechanics force fields are widely used in computer-aided drug design for the study of drug-like molecules alone or interacting with biological systems. In simulations involving biological macromolecules, the biological part is typically represented by a specialized biomolecular force field, while the drug is represented by a matching general (organic) force field. In order to apply these general force fields to an arbitrary drug-like molecule, functionality for assignment of atom types, parameters, and charges is required. In the present article, which is part I of a series of two, we present the algorithms for bond perception and atom typing for the CHARMM General Force Field (CGenFF). The CGenFF atom typer first associates attributes to the atoms and bonds in a molecule, such as valence, bond order, and ring membership among others. Of note are a number of features that are specifically required for CGenFF. This information is then used by the atom typing routine to assign CGenFF atom types based on a programmable decision tree. This allows for straightforward implementation of CGenFF's complicated atom typing rules and for equally straightforward updating of the atom typing scheme as the force field grows. The presented atom typer was validated by assigning correct atom types on 477 model compounds including in the training set as well as 126 test-set molecules that were constructed to specifically verify its different components. The program may be utilized via an online implementation at https://www.paramchem.org/ .