Scalable Density-Based Local and Global Classifications of Noncovalent Interactions

Abstract

Noncovalent interactions play a central role in chemistry, biology, and materials science, governing processes ranging from molecular recognition and protein folding to crystal packing and supramolecular assembly. The rational design of these interactions relies on principles such as directionality and complementarity, which control the organization and stability of molecular complexes. Although energetic decomposition analyses can provide insight into these features, their computational cost limits their application to large-scale systems. Here, we introduce a simple density-based descriptor,qNCIVvdW, that quantifies interaction localization and captures the balance between electrostatic and dispersion contributions. The descriptor can be evaluated globally for complete complexes or locally for individual interaction regions, requiring only structural information and avoiding computationally demanding energy partitioning schemes. This provides a scalable framework for characterizing and designing noncovalent interactions across molecular systems ranging from small complexes to large supramolecular architectures.