Similarity scores of vibrational spectra reveal the atomistic structure of pentapeptides in multiple basins

Vibrational spectroscopy combined with theoretical calculations is a powerful tool to reveal the interaction and conformation of peptides at the atomistic level. Despite the advances in experimental techniques, theoretical calculations have become increasingly challenging as the molecule of interest grows complex. Here, we propose a novel conformational search method, which exploits the structure-spectrum correlation using a similarity score that quantifies the agreement of theoretical and experimental spectra. The method reveals the atomistic structure of two conformers of a capped penta-peptide, acetyl-SIVSF-N-methylamine, which has remained unknown since its first observation [Angew. Chem. Int. Ed. 2018, 57, 5626]. Although one of the conformers is assigned to the lowest-energy conformer, the other one is found to be 25 kJ mol-1 higher in energy with distinctly different geometry. The result suggests multiple pathways in the early stage of the folding process; one to the global minimum and the other to a different basin. Once such a structure is formed, the second conformer hardly overcomes the barrier to produce the most stable structure due to a vastly different hydrogen bond network of the backbone. The proposed method can characterize not only the lowest-energy conformer but also kinetically trapped, high-energy conformers of complex biomolecules.