Voltage Sensitivity of Indocyanine Green in Polarized Membranes: A Computational Study

Indocyanine green (ICG) is an amphiphilic, near-infrared, FDA-approved fluorescent dye with established voltage sensitivity in biomembranes, making it a promising candidate for voltage sensing and imaging, particularly in neurons where action potentials drive dynamic changes in membrane potential. In this study we investigate the molecular determinants of ICG's voltage sensitivity in polarized lipid membranes. Combining molecular simulations with electronic structure calculations, we analyze how the membrane environment modulates ICG's photoabsorption, a step preceding fluorescent emission. Our findings reveal that the optical response of the dye to the transmembrane potential is indirect: the transmembrane potential not only influences the dye's localization within the membrane but also affects its immediate charge environment, ultimately driving the electrochromic spectral shift. A key feature of our approach is the inclusion of the inhomogeneous charge environment arising from membrane polarization in the optical response calculations. We show that accurately capturing the dye's photoabsorption response to a change in the membrane voltage requires a detailed atomistic description of the dye-lipid Coulomb interactions, beyond the scope of homogeneous field approximations or continuum solvation models.