Conformational analysis of an acyclic tetrapeptide: ab‐initio structure determination from X‐ray powder diffraction, Hirshfeld surface analysis and electronic structure

A terminally protected acyclic tetrapeptide has been synthesized, and the crystal structure of its hydrated form, Boc‐Tyr‐Aib‐Tyr‐Ile‐OMe·2H 2 O ( 1 ), has been determined directly from powder X‐ray diffraction data. The backbone conformation of tetrapeptide ( 1 ) exhibiting two consecutive β‐turns is stabilized by two 4 → 1 intramolecular N―H · · · O hydrogen bonds. In the crystalline state, the tetrapeptide molecules are assembled through water‐mediated O―H · · · O hydrogen bonds to form two‐dimensional molecular sheets, which are further linked by intermolecular C―H · · · O hydrogen bonds into a three‐dimensional supramolecular framework. The molecular electrostatic potential (MEP) surface of ( 1 ) has been used to supplement the crystallographic observations. The nature of intermolecular interactions in ( 1 ) has been analyzed quantitatively through the Hirshfeld surface and two‐dimensional fingerprint plot. The DFT optimized molecular geometry of ( 1 ) agrees closely with that obtained from the X‐ray structure analysis. The present structure analysis of Boc‐Tyr‐Aib‐Tyr‐Ile‐OMe·2H 2 O ( 1 ) represents a case where ab‐initio crystal structure of an acyclic tetrapeptide with considerable molecular flexibility has been accomplished from laboratory X‐ray powder diffraction data. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.