Elucidating Solution Structures of Cyclic Peptides Using Molecular Dynamics Simulations

Protein-protein interactions are vital to biological processes, but the shape and size of their interfaces make them hard to target using small molecules. Cyclic peptides have shown promise as protein-protein interaction modulators, as they can bind protein surfaces with high affinity and specificity. Dozens of cyclic peptides are already FDA approved, and many more are in various stages of development as immunosuppressants, antibiotics, antivirals, or anticancer drugs. However, most cyclic peptide drugs so far have been natural products or derivatives thereof, with de novo design having proven challenging. A key obstacle is structural characterization: cyclic peptides frequently adopt multiple conformations in solution, which are difficult to resolve using techniques like NMR spectroscopy. The lack of solution structural information prevents a thorough understanding of cyclic peptides' sequence-structure-function relationship. Here we review recent development and application of molecular dynamics simulations with enhanced sampling to studying the solution structures of cyclic peptides. We describe novel computational methods capable of sampling cyclic peptides' conformational space and provide examples of computational studies that relate peptides' sequence and structure to biological activity. We demonstrate that molecular dynamics simulations have grown from an explanatory technique to a full-fledged tool for systematic studies at the forefront of cyclic peptide therapeutic design.