FMOe: Preprocessing and Visualizing Package of the Fragment Molecular Orbital Method for Molecular Operating Environment and Its Applications in Covalent Ligand and Metalloprotein Analyses

The fragment molecular orbital (FMO) method is an efficient quantum chemical calculation technique for large biomolecules, dividing each into smaller fragments and providing inter-fragment interaction energies (IFIEs) that support our understanding of molecular recognition. The ab initio fragment MO method program (ABINIT-MP), an FMO processing software, can automatically divide typical proteins and nucleic acids. In contrast, small molecules such as ligands and hetero systems must be manually divided. Thus, we developed a graphical user interface to easily handle such manual fragmentation as a library for Molecular Operating Environment (MOE) that preprocesses and visualizes FMO calculations. We demonstrated fragmentation with IFIE analyses for the two following cases: 1) covalent cysteine–ligand bonding inside the SARS-CoV-2 main protease (Mpro) and nirmatrelvir (Paxlovid) complex, and 2) the metal coordination inside a zinc-bound cyclic peptide. IFIE analysis successfully identified the key amino acid residues for the molecular recognition of nirmatrelrvir with Mpro and the details of their interactions (e.g., hydrogen bonds and CH/π interactions) via ligand fragmentation of functional group units. In metalloproteins, we found an efficient and accurate scheme for the fragmentation of Zn2+ ions with four histidines coordinated to the ion. FMOe simplifies manual fragmentation, allowing users to experiment with various fragmentation patterns and perform in-depth IFIE analysis with high accuracy. In the future, our findings will provide valuable insight into complicated cases, such as ligand fragmentation in modality drug discovery, especially for medium-sized molecules and metalloprotein fragmentation around metals.