Unveiling Hidden Intramolecular Non-Covalent Interactions in a Neutral Serine, Its Zwitterion, Cluster, and Crystal by Features of Electron Density

Abstract

We investigate intramolecular non-covalent interactions (NCIs) in neutral serine, its zwitterion, molecular clusters, and crystal using electron density-based approaches, including QTAIM, RDG, IQA, and electronic pressure analysis. In addition to completed NCIs (hydrogen bonds with bond paths), we identify latent interactions—attractive, bond-path-free atomic pair interactions with negative interaction energies. These are classified into dynamic (vibration-induced and transient) and static (secondary, persistent but structurally passive) types. Analysis of the internal pressure in electronic continuum reveals that latent NCIs exhibit distinct signatures in the kinetic and exchange components, which evolve across the molecular, cluster, and crystalline states. Dynamic interactions are characterized by off-axis minima in the exchange part of the pressure, whereas static interactions lack such features. Upon crystallization, intramolecular latent NCIs may disappear due to electron density redistribution and the formation of intermolecular hydrogen bonds. These intermolecular contacts may also spatially constrain atoms, suppressing vibrational flexibility and effectively converting dynamic NCIs into static ones. The kinetic pressure highlights regions of electron localization, while the exchange pressure offers a physical criterion for distinguishing different types of NCIs. Our findings demonstrate the structural and stabilizing roles of latent interactions and establish electronic pressure as a sensitive and informative descriptor for their analysis.