Expanding the versatility of natural and de novo designed coiled coils and helical bundles

Natural helical bundles (HBs) constitute a ubiquitous class of protein folds built of two or more longitudinally arranged α-helices. They adopt topologies that include symmetric, highly regular assemblies all the way to asymmetric, loosely packed domains. The diverse functional spectrum of HBs ranges from structural scaffolds to complex and dynamic effectors as molecular motors, signaling and sensing molecules, enzymes, and molecular switches. Symmetric HBs, particularly coiled coils, offer simple model systems providing an ideal entry point for protein folding and design studies. Herein, we review recent progress unveiling new structural features and functional mechanisms in natural HBs and cover staggering advances in the de novo design of HBs, giving rise to exotic structures and the creation of novel functions. •Natural α-helical bundles (HBs) display complex structure-function relationships.•HBs are amenable to rational design.•De novo designed HBs show exotic folds without natural counterparts.•Recent design advances have created HBs with strong therapeutic potential de novo.