Synthetic Biology for Designing Allostery and Its Potential Biomedical Applications.

Allosteric regulation of protein function, where a perturbation at one site induces a conformational shift or alters dynamics at a distal functional site, plays a key role in numerous biological processes. The ability to introduce allostery using synthetic biology principles holds significant potential both for biomedical and biotechnological applications, and for advancing our understanding of natural allostery. By customizing target proteins for sensing specific chemical or physical signals, including ligand binding and environmental cues, we aim to allosterically modulate the function of a target protein depending on the selected triggers. This approach, unlike active-site targeting, offers greater specificity and selectivity and can allosterically couple diverse physiological processes. Synthetic biology strategies have been developed recently for designed allosteric protein regulation, including the design of allosteric modulators such as domain insertion, generation of de novo allosteric protein switches, and application of engineered allosteric mechanisms to control cellular functions. We examine the application of artificial intelligence (AI)-based generative protein design and other important milestones, challenges and opportunities in this field, highlighting how these approaches could be applied for the development of new therapeutic strategies.