Probing the Influence of Sulfur–Aromatic Interactions on the Electronic Structure of Gas‐Phase Peptides

ABSTRACT Non‐covalent sulfur–aromatic () interactions play a crucial role in stabilizing the structure of proteins and have been associated with neurodegenerative diseases. We investigated the influence of the interaction on the electronic structure and fragmentation behavior of sequence‐isomer model peptides by means of ultraviolet photodissociation (UVPD) and near‐edge x‐ray absorption mass spectrometry (NEXAMS). The studies revealed distinct fragmentation behavior for one of the model peptides under both valence and core–shell electronic excitation, with characteristic fragmentation channels that serve as potential fingerprints of sulfur–aromatic interactions. Moreover, core–shell excitations at the carbon K‐edge revealed significant shifts between the peptide and the control peptides in the aromatic transitions, indicating changes in the electronic structure due to interactions. Enhanced sampling molecular dynamics and quantum mechanical calculations reveal the influence of the sulfur orientation, providing insights into the fundamental nature of interactions.