Stickiness of the Hydrogen Bond

The dielectric response of bulk water follows laws of continuum electrostatics, a scheme often extrapolated without justification to treat confined interfacial water, where the Debye polarization ansatz breaks down and discrete effects matter. Reconciling the discrete behavior with the continuum equations requires a conceptual leap, all the more so when assessing the electrostatic impact of exclusion of individual water molecules. This work takes up the challenge and identifies the nanoscale stickiness of a preformed water‐embedded hydrogen bond as phenomena not encompassed by continuum laws but quantitatively predictable when adopting a nanoscale theory of dielectric response holding down to molecular dimensions. Nanoscale stickiness is known to drive basic cellular events and has been measured using a molecular force probe but its physical underpinnings and computation have been lacking so far. The findings reported may impact molecular design in bio‐nanotechnology and shed light on standing challenges in biophysics, especially on the protein folding problem, where organized compaction of the protein chain following nucleating intramolecular hydrogen bonding demands explanation.