LAUSR

Abstract Depsipeptides are naturally occurring peptide analogues containing ester functionalities and are in the focus of numerous pharmaceutical researches and clinical studies owing to their enzyme inhibitor properties and cytotoxic activity against human tumor cell lines. Exploring their conformational landscape could contribute to a better understanding of their mechanism of action and support further drug developments. In this article, we present a combined theoretical and experimental study of the Ac(-Ala)1–4-OMe depsipeptide series by means of matrix-isolation (MI) IR and VCD spectroscopy. The conformational spaces of these peptides were explored via molecular mechanics and DFT computations and the IR and VCD spectra of isolated molecules were recorded in low-temperature Ar matrices. It is demonstrated that MI-VCD spectroscopy can provide additional information even to well resolved MI-IR spectra and support the determination of conformer distributions. Three conformers of Ac-Ala-OMe were identified experimentally, in agreement with theoretical predictions, and their approximate relative ratios were determined. In the case of larger members of the series, the unambiguous identification of individual conformers was not possible in most cases. However, simultaneous analysis of MI-VCD and MI-IR spectra allowed the assignment of the spectral signatures of typical secondary structural elements and groups of similar conformers. The effects including empirical dispersion corrections in DFT computations on the conformer distribution were also examined.