Protein-Protein Interactions with the Fragment Molecular Orbital Method.

Protein-protein interactions (PPIs) are essential for the function of many proteins, and their dysregulation contributes to a wide range of diseases. As such, PPIs have emerged as challenging yet promising targets for drug discovery. However, the structural and energetic complexity of PPIs has limited the success of traditional small-molecule strategies, underscoring the need for accurate and interpretable computational tools to characterize interfacial energetics. The fragment molecular orbital (FMO) quantum mechanics method offers a comprehensive and computationally inexpensive means of identifying the strength and the chemical nature of the molecular interactions taking place at the protein-protein interface of large biomolecular systems. The application of FMO to protein-protein interfaces enables residue-level identification of binding hotspots and classification of key energetic contributions, including direct, intramolecular, and water-mediated interactions.