Mode-Selective Terahertz Modulation of Bicarbonate Binding in Band 3/Anion Exchanger 1.

Resonant terahertz (THz) excitation can modulate ligand binding through selective vibrational driving rather than nonspecific heating alone, but whether distinct local vibrations at the same binding site affect binding stability differently remains unclear. Here, we combine all-atom molecular dynamics, hydrogen-bond analysis, and potential of mean force calculations to examine how THz fields matched to distinct binding-associated vibrations modulate the coordination of bicarbonate (HCO3-) at Arg730 (R730) in Band 3/anion exchanger 1. Vibrational analysis identifies two HCO3--coupled guanidinium motions, Nη-proton wagging and hydrogen-bonded N-H stretching. Frequency-matched excitation selectively amplifies these coordinates, shortening R730-HCO3- hydrogen-bond persistence, shifting the ensemble away from bidentate coordination, and reducing the local dissociation barrier. The two modes are not functionally equivalent. At the higher field strength, excitation of the N-H stretching mode produces the larger loss of bound-state stabilization. An off-resonance control does not reproduce these responses. These results establish mode-selective vibrational modulation of a defined protein-ion interaction, providing a molecular basis for frequency-targeted control of biomolecular recognition.