Determining the Predominant Conformations of Mortiamides A-D in Solution Using NMR Data and Molecular Modeling Tools

Macrocyclic peptidomimetics have been seriously contributingtoour arsenal of drugs to combat diseases. The search for nature'sdiscoveries led us to mortiamides A-D (found in a novel fungusfrom Northern Canada), which is a family of cyclic peptides that clearlyhave demonstrated impressive pharmaceutical potential. This promptedus to learn more about their solution-state properties as these arecentral for binding to target molecules. Here, we secured and isolatedmortiamide 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-bondand through-space) data to confirm the primary structure, and NMR-drivenmolecular dynamics (MD) simulations suggested that more than one predominantthree-dimensional (3D) structure exist in solution. Further stepsof MD simulations are consistent with the finding that the backbonesof mortiamides A-C also have at least two prominent macrocyclicshapes, but the side-chain structures and dynamics differed significantly.Knowledge of these solution properties can be exploited for drug designand discovery.

Automated summary

Macrocyclic peptidomimetics have made significant contributions to drug development. The discovery of mortiamides A-D, cyclic peptides with pharmaceutical potential, has led to further study of their solution-state properties. Nuclear magnetic resonance data and molecular dynamics simulations have shown that these peptides have multiple three-dimensional structures in solution. Understanding these properties can aid in drug design and discovery.