A Generally Applicable Method for Disentangling the Effect of Individual Noncovalent Interactions on the Binding Energy

Abstract

We introduce the fragment‐pairwise Local Energy Decomposition (fp‐LED) scheme for precise quantification of individual interactions contributing to the binding energy of arbitrary chemical entities, such as protein‐ligand binding energies, lattice energies of molecular crystals, or association energies of large biomolecular assemblies. Using fp‐LED, we can assess whether the contribution to the binding energy arising from noncovalent interactions between pairs of molecular fragments in any chemical system is attractive or repulsive, and accurately quantify its magnitude at the coupled cluster level ‐ commonly considered as the “gold standard” of computational chemistry. Such insights are crucial for advancing molecular and material design strategies in fields like catalysis and therapeutic development. Illustrative applications across diverse fields demonstrate the versatility and accuracy of this theoretical framework, promising profound implications for fundamental understanding and practical applications.