The Fragment Molecular Orbital (FMO) method is a computational approach used to study the interactions between a ligand and a protein by breaking down large molecular systems into smaller, more manageable fragments. This method allows for the application of quantum mechanical calculations to systems that would otherwise be too large and computationally demanding. The FMO method was developed to compute very large molecular systems by dividing them into fragments and performing ab initio or density functional theory (DFT) calculations on these smaller units. his approach enables the study of complex biomolecular interactions, including protein-ligand binding, by providing detailed insights into the chemical nature of each residue and water molecule's contribution to ligand binding. FMO offers faster computational speeds than traditional quantum-mechanical (QM) methods and provides accurate information for investigating the chemical nature and binding characteristics of protein-ligand interactions. It is particularly useful for revealing atomistic details about individual contributions toward ligand binding, which are difficult to detect without using QM methods. The FMO method can be applied to structure-based drug design (SBDD) processes, as it allows for the rationalization of affinity and selectivity in ligand binding. By analyzing crystal structures of receptors with their corresponding agonists and antagonists, FMO can provide valuable insights for computer-aided drug design (CADD). FMO-based Pair Interaction Energy Decomposition Analysis (PIEDA) provides a breakdown of interaction energies into components such as electrostatic, exchange, charge transfer, and dispersion contributions. This detailed analysis helps identify key residues and interactions critical for binding. The FMO method is implemented in software packages like GAMESS (US), ABINIT-MP, PAICS, and OpenFMO, which are distributed free of charge .