fourhelix

Fourhelix is a descriptor used in structural biology to denote a protein fold composed of four alpha helices arranged into a compact, globular bundle. The motif is a simple, all-helical design that occurs in many natural proteins as well as in engineered constructs.

Structural features of a four-helix bundle include a hydrophobic core formed by inward-facing side chains on the helices, surrounded by more polar surfaces. The helices can adopt parallel or antiparallel orientations, leading to several topologies such as an up-and-down arrangement or layered packing. The compact geometry typically supports stability and compact folding.

Distribution and function: Four-helix bundles are found across all domains of life. They serve as modular scaffolds for diverse roles, including small enzymes, regulatory domains, and protein–protein interaction modules. In some instances they act as oligomerization interfaces, enabling dimeric or tetrameric assemblies that contribute to functional complex formation.

Biotechnological relevance: Because of their stability and designability, four-helix bundles are popular scaffolds in protein engineering. Researchers use them as starting points for de novo design, exploring folding principles, mutational tolerance, and the creation of novel binding sites, signaling modules, or metal-coordination motifs.

Classification and terminology: In structural classifications such as SCOP and CATH, four-helix bundle motifs are recognized as a single-domain fold with multiple superfamilies. The motif illustrates how a simple four-helix arrangement can support a wide range of functions through variations in topology and sequence.