Topological Investigation of Protein Folding and Intrinsic Disorder

Mapping protein conformations into a space of fold topologies offers an unprecedented perspective on the long-standing protein folding problem. In this study, we apply circuit topology to investigate the folding landscape of both stably folded and intrinsically disordered proteins. This topological approach quantifies intra-chain contact arrangements within a polypeptide chain. We demonstrate that ordered and disordered proteins can be distinguished by their topological organization, and that a topology-based model can predict chain compaction and folding state. Furthermore, topology relates to folding and unfolding kinetics and thermodynamics. These findings establish topology as a fundamental concept for understanding protein folding and disorder.