Ligand‐Induced Electronic Response Enables Predictive QM/MM Simulations

ABSTRACT Predictive modeling of large molecular systems demands methods that combine quantum accuracy with scalability. Although hybrid quantum mechanics/molecular mechanics (QM/MM) simulations offer such a framework, their predictive power has been limited by the subjective and system‐specific definition of the QM region. Here, we present an electronically informed protocol that objectively defines QM regions from ligand‐induced orbital shifts and charge‐redistribution, extracted in a single semiempirical fragment molecular orbital (FMO) calculation. Validated on both zeolite–guest and enzyme–inhibitor complexes, the method achieves chemical accuracy (within ∼1–2 kcal/mol on binding energies) while substantially reducing computational cost at the DFTB level. This cross‐domain strategy reframes QM/MM as a transferable design principle, bridging solid‐state catalysis and quantum biochemistry, and thereby providing a practical platform for predictive molecular engineering across diverse disciplines.