Exploring the Conformational Landscape of Complexes with Cucurbit[8]uril and Aromatic Peptide Dimers by Ion Mobility Mass Spectrometry and Theoretical Calculations

Precise control of peptide dimerization holds profound implications for elucidating biological functions, advancing drug design, and engineering self-assembling materials. Significant progress has been achieved in cucurbit[8]uril (CB[8])-mediated dimerization of canonical aromatic peptides (XGG, X = F (Phe)/Y (Tyr)/W (Trp), G = Gly), and further conformational exploration is crucial for the determination of potential applications. In this work, we conduct gas-phase structural characterization of complexes with CB[8] and XGG dimers by ion mobility mass spectrometry (IM-MS) and theoretical calculations, with particular attention to the dependence of the conformational landscape and noncovalent interaction (NCI). IM-MS and MS² experiments reveal the conformational diversity, dissociation pathways, and stability differences of the complexes of CB[8] and XGG homo/heterodimers. Theoretical calculations elucidate the topological morphologies and geometry details of complexes and categorize them into the <i>Hourglass</i>, <i>Boot</i>, and <i>S-type</i> conformers based on the orientation of peptide chains at the CB[8] port. Visualization of NCIs and energy decomposition analysis (EDA) reveal the intriguing trends in intermolecular interactions and energy contribution terms across conformers of distinct morphologies. Our work provides insights for guiding the design of the supramolecular junction for specific control of the peptide spatial behavior.