Biological Active Region Defined by Fragment-based Molecular Theory

Computational chemistry studies using the QM/MM approach have been conducted to explain and predict protein functions. However, the active regions responsible for those functions often need to be clarified. In this paper, we propose a simple method to define the active region of a ligand from its physicochemical components using the fragment molecular orbital theory. This method systematically determines the QM region in QM/MM calculations by considering quantum interactions among amino acid residues, i.e., charge transfer relays. Within proteins, the relays occur through the interaction network formed among residues, and this phenomenon may interfere with the determination of the QM region. We determined the quantum chemical active region by analyzing the difference in the charge transfer relay upon ligand binding to the protein. Defining the active region as the domain where these relays converge, we successfully reproduce the experimental activity qualitatively; our definition of the active region is reliable. The proposed method defines the QM region easily and unambiguously and is expected to aid in bio-relevant chemistry and drug discovery.