Few protein structures feature knotted or interlocked backbones. Lasso peptides are a remarkable class of natural products that have a unique macrocyclic ring with a linear tail threaded through the center, emulating the shape of a lasso. These peptides offer a unique starting point to serve as a scaffold for creating new constrained structures, such as interlocked ring (catenane) molecular knots. Through mutagenesis and digestion, lasso peptides can be cleaved in desired locations to form rotaxanes. By employing bioconjugate chemistries on these rotaxanes, we can alter the shape of these molecules by introducing new chemical linkages to connect the cleaved chains back together. Using a combination of enzymatic reactions and NMR, we can probe these reaction products to confirm the new topologies. We will present the results of our efforts to rearrange lasso architectures into small peptide catenanes, and describe other potential applications for this experimental approach to alter lasso peptide structure and function.

Bending lasso peptide structure

249th National Meeting (2015)

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