Macrocyclic peptidomimetics have been seriously contributing to our arsenal of drugs to combat diseases. The search for nature's discoveries led us to mortiamides A-D (found in a novel fungus from Northern Canada), which is a family of cyclic peptides that clearly have demonstrated impressive pharmaceutical potential. This prompted us to learn more about their solution-state properties as these are central for binding to target molecules. Here, we secured and isolated mortiamide D, and then acquired high-resolution nuclear magnetic resonance (NMR) data to learn more about its structure and dynamics attributes. Sets of two-dimensional NMR experiments provided atomic-level (through-bond and through-space) data to confirm the primary structure, and NMR-driven molecular dynamics (MD) simulations suggested that more than one predominant three-dimensional (3D) structure exist in solution. Further steps of MD simulations are consistent with the finding that the backbones of mortiamides A-C also have at least two prominent macrocyclic shapes, but the side-chain structures and dynamics differed significantly. Knowledge of these solution properties can be exploited for drug design and discovery.

Departement de Chimie and PROTEO Faculté des Sciences et de Génie Université Laval 1045 Avenue de la Médecine Québec Quebec G1V OA6 Canada

Department of Chemistry Faculty of Science University of Hradec Králové Rokitanskeho 62 50003 Hradec Králové Czech Republic

Department of Chemistry Federal Institute of Espírito Santo Unit Vila Velha 29106 010 Vila Velha ES Brazil

INRS Centre Armand Frappier Santé Biotechnologie Université de Québec 531 Boulevard des Prairies Laval Quebec H7V 1B7 Canada

Laboratory of Molecular Modeling Applied to Chemical and Biological Defense Military Institute of Engineering 22290 270 Rio de Janeiro Brazil

NMR consultant of Steven R LaPlante's Lab INRS Centre Armand Frappier Santé Biotechnologie Université de Québec 531 Boulevard des Prairies Laval Quebec H7V 1B7 Canada

PPGQUI Federal University of Espírito Santo Av Fernando Ferrari 514 29075 910 Vitória ES Brazil

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