Nonfolding

Nonfolding is a general descriptor used across disciplines to refer to systems, molecules, or states that do not adopt a stable, well-defined folded structure. It contrasts with the common view of folding as a process by which a molecule achieves a specific, energetically favorable three-dimensional arrangement.

In biology, nonfolding often relates to intrinsically disordered proteins or regions that lack a single fixed structure under physiological conditions. These disordered components can be highly dynamic, sampling a range of conformations and sometimes undergoing structural changes upon binding to partners or in response to environmental cues. Nonfolding in this sense does not imply a failure of function; rather, it reflects a functional flexibility that can be essential for signaling, regulation, and interaction networks. Denatured states or molten globule forms represent other nonfolded conformations that may occur under stress or in vitro conditions.

In chemistry and polymer science, nonfolding describes polymers or small molecules that do not form compact intramolecular folds under given conditions. Factors such as chain rigidity, solvent quality, temperature, and ionic strength influence folding propensity. Some synthetic polymers are designed to remain extended or to form specific non-folded arrangements to achieve desired rheological properties, catalytic environments, or self-assembly behaviors.

Detection and study of nonfolding typically involve spectroscopic and calorimetric methods that reveal the absence of characteristic folded-state signatures, along with techniques like nuclear magnetic resonance and single-molecule studies that illustrate conformational dynamics.

Nonfolding is a descriptive term rather than a formal classification. It encompasses a range of phenomena, from unfolded protein states and intrinsically disordered regions to nonfolded polymers, and highlights the diversity of structural behavior beyond canonical folding.