Residual dipolar couplings in short peptidic foldamers: Combined analyses of backbone and side-chain conformations and evaluation of structure coordinates of rigid unnatural amino acids

In summary, we have presented an RDC-based approach to select appropriate structures for the force-field parameterization of rigid nonstandard amino acids. Conformational analyses of H-(L)-Pro-(L)-Pro-▼-OBn show that even slight alterations in the proton positions of unnatural amino acids can lead to significant deviations in backbone and side-chain conformations. In the presence of cis-β-ACC as a probe for molecular alignment, RDCs allowed us to obtain conformational information on the backbone of the short linear peptide H-(L)-Pro-▼-(L)-Pro-OBn, being especially valuable if the NOE analysis is affected by chemical exchange. In addition, RDCs were employed to detect the preferences of proline side-chain conformations. This study shows that even in the case of short linear peptides with unnatural amino acids, RDCs at natural abundance can provide essential structural information. This example demonstrates that the RDC approach can be expanded to open-chain structures not only in the case of configuration determination, but also in the field of conformational analyses. In the context of β-ACC, RDC-supported conformational studies are expected to help establish the structure activity/selectivity relationships of neuropeptide Y (NPY) analogues, integrin ligands and organocatalysts that have been developed with this amino acid.