Coiled Coils as a Programmable Platform for Computational Biosensor Design

Coiled coils are a versatile class of α‐helical protein motifs characterized by recurring sequence patterns that direct their assembly into defined oligomeric bundles and underpin a wide range of biological functions. The well‐established sequence‐structure relationships governing coiled‐coil formation enable predictive control over stability, specificity, and oligomerization state, making them attractive and chemically tractable building blocks for biosensor design in applications ranging from single‐molecule detection to synthetic biochemical circuits and functional nanomaterials. After revisiting the theoretical foundations of coiled‐coil architecture, this review outlines strategies to engineer programmable binding interfaces that can be rationally tuned to generate orthogonal, high–affinity interaction pairs, enabling flexible and modular biosensor platforms. Particular emphasis is placed on recent advances in computational and data‐driven design approaches, including machine‐learning and AI‐based strategies, alongside established rational and empirical methods for coiled‐coil construction. These complementary design principles underpin the development of coiled‐coil‐based biosensors and are discussed together with selected application examples to illustrate how engineered coiled‐coil interactions support sensitive and specific molecular recognition as well as switchable control in synthetic biology and chemical biology. Overall, this review highlights coiled coils as programmable, stable, and highly designable scaffolds at the interface of molecular engineering, computation, and chemical biology.