Comprehensive Quantum Chemical Interaction Analysis of Whole Protein–Ligand Structures in BindingDB Using the Fragment Molecular Orbital Method
Year: 2026
Type: preprint
Abstract: Understanding protein–ligand interactions based on their electronic states is important for elucidating molecular recognition and supporting structure-based drug discovery. In this study, we performed fragment molecular orbital (FMO) calculations, a quantum chemical approach, for a comprehensive set of experimentally determined protein–ligand complexes derived from BindingDB. Ligand–amino acid residue interactions were quantitatively characterized using inter-fragment interaction energies (IFIEs) and pair interaction energy decomposition analysis (PIEDA), and were compared with molecular mechanics (MM) interaction energies. The comparison revealed residue- and interaction-dependent differences between the FMO and MM descriptions, with particularly distinct behavior for interactions involving aromatic residues. Comprehensive IFIE/PIEDA analysis further revealed characteristic energetic contributions associated with amino acid residue type and ligand charge, including dispersion contributions involving aromatic residues and charge-transfer contributions associated with hydrogen-bonding interactions. A case study of MAPK14 demonstrated that the resulting dataset can identify residue regions commonly involved in ligand recognition and distinguish residue-level interaction patterns among individual ligands. These results provide a systematic quantum chemical perspective on diverse protein–ligand interactions and establish a quantum chemical resource for complementing structural, experimental, and conventional MM-based analyses.
Source: ChemRxiv
Language: English
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214724145