Coil–Globule versus Field-Driven Coil–Blob Transitions of PEG under Nanopore Confinement

Abstract Poly(ethylene glycol) (PEG) undergoes a coil–globule transition above its lower critical solution temperature (LCST) as hydration weakens. While this behavior is commonly tuned using chemical modification or cosolutes, nanoscale confinement provides an alternative physical means by which to influence polymer properties. Here, we use nanopore-based size discrimination as an indicator of full polymer confinement to track driven conformational transitions at the single-polymer level by examining the temperature-dependent transport of polydisperse PEGs (1500, 2000, and 3400 g·mol–1) through two β-barrel protein nanopores with distinct geometries and surface properties: α-hemolysin (α-HL) and aerolysin (Ael), over the temperature range 5–45 °C. While temperature does not affect nanopore structure, it strongly modulates PEG–nanopore interaction kinetics. In α-HL, blockade durations for larger PEGs increase strongly with temperature, enabling size discrimination of PEG 2000 above 25 °C and PEG 3400 at 45 °C, consistent with a confinement-induced coil–globule transition and a reduced apparent LCST. In contrast, in Ael, blockade durations decrease with temperature for all PEG sizes, restricting size discrimination to low temperatures under high applied voltages. This behavior, although our observations are inferred from transport dynamics rather than direct structural measurements, indicates a field-driven, blob-like polymer confinement, in which the chain is forced into the nanopore by the electric field rather than stabilized by thermodynamics. These contrasting regimes are rationalized by using scaling arguments and a unified free-energy framework for polymer confinement.