Abstract
Molecular modeling and simulation serve an important role in exploring biological functions of proteins at the molecular level, which is complementary to experiments. CHARMM-GUI (https://www.charmm-gui.org) is a web-based graphical user interface that generates complex molecular simulation systems and input files, and we have been continuously developing and expanding its functionalities to facilitate various complex molecular modeling and make molecular dynamics simulations more accessible to the scientific community. Currently, covalent drug discovery emerges as a popular and important field. Covalent drug forms a chemical bond with specific residues on the target protein, and it has advantages in potency for its prolonged inhibition effects. Even though there are higher demands in modeling PDB protein structures with various covalent ligand types, proper modeling of covalent ligands remains challenging. This work presents a new functionality in CHARMM-GUI PDB Reader & Manipulator that can handle a diversity of ligand-amino acid linkage types, which is validated by a careful benchmark study using over 1,000 covalent ligand structures in RCSB PDB. We hope that this new functionality can boost the modeling and simulation study of covalent ligands.