Conformational diversity or “shapeshifting” in cyclic peptide natu- ral products can, in principle, confer a single molecular entity with the proper- ty of binding to multiple receptors. Conformational equilibria have been probed in the contryphans, which are peptides derived from Conus venom possessing a 23-membered cyclic disul- fide moiety. The natural sequences derived from Conus inscriptus , GCV D LYPWC* (In936) and Conus lor- oisii , GCP D WDPWC* (Lo959) differ in the number of proline residues within the macrocyclic ring. Structural charac- terisation of distinct conformational states arising from cis – trans equilibria about Xxx–Pro bonds is reported. Iso- merisation about the C2–P3 bond is observed in the case of Lo959 and about the Y5–P6 bond in In936. Evi- dence is presented for as many as four distinct species in the case of the syn- thetic analogue V3P In936. The Tyr- Pro-Trp segment in In936 is character- ised by distinct sidechain orientations as a consequence of aromatic/proline interactions as evidenced by specific sidechain–sidechain nuclear Overhaus- er effects and ring current shifted proton chemical shifts. Molecular dy- namics simulations suggest that Tyr5 and Trp7 sidechain conformations are correlated and depend on the geometry of the Xxx–Pro bond. Thermodynamic parameters are derived for the cis $ trans equilibrium for In936. Studies on synthetic analogues provide insights into the role of sequence effects in modulating isomerisation about Xxx– Pro bonds.

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