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

Abstract

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.