The Heterogeneity Principle: Interaction Diversity as the Primary Driver of Supramolecular Stability

The rational design of stable supramolecular systems has long relied on the “stronger is better” paradigm, prioritizing maximum individual interaction strengths. This approach, however, fails to explain the frequent disconnect between binding energies and macroscopic properties such as kinetic stability and viscosity. Here, this study challenges this fundamental assumption through a comprehensive statistical analysis of 2,649 quantum-chemically optimized molecular complexes spanning hydrogen bonding, π-stacking, and dispersion interactions. Using the Kulkarni-NCI Fingerprint (KNF), a physics-informed 9-dimensional descriptor, we systematically deconstructed the relationship between molecular architecture and three distinct stability metrics: local interaction quality (SNCI), global binding energy, and electrostatic interactions (SCDI). Our analysis reveals a profound paradigm shift: supramolecular stability is not primarily governed by average interaction strength but by interaction heterogeneity—the standard deviation of the non-covalent interaction field. This “Heterogeneity Principle” demonstrates a robust positive correlation (r = 0.643, p < 10−25) between architectural diversity and local stability, while exhibiting opposite correlations with global metrics, revealing fundamental physical trade-offs. Systematic causation analysis, including confounding variable control and dose-response validation, provides moderate-to-strong evidence (causation score: 0.59) for genuine causal relationships. Stratification analysis confirms a monotonic dose-response pattern, with high-heterogeneity systems achieving 2.36-fold enhanced stability compared to homogeneous architectures. These findings establish quantitative design principles predicting 295% stability enhancements through rational heterogeneity optimization, fundamentally transforming supramolecular design from strength-focused to diversity-driven strategies.