Light
sensing in photoreceptor proteins is subtly modulated by
the multiple interactions between the chromophoric unit and its binding
pocket. Many theoretical and experimental studies have tried to uncover
the fundamental origin of these interactions but reached contradictory
conclusions as to whether electrostatics, polarization, or intrinsically
quantum effects prevail. Here, we select rhodopsin as a prototypical
photoreceptor system to reveal the molecular mechanism underlying
these interactions and regulating the spectral tuning. Combining a
multireference perturbation method and density functional theory with
a classical but atomistic and polarizable embedding scheme, we show
that accounting for electrostatics only leads to a qualitatively wrong
picture, while a responsive environment can successfully capture both
the classical and quantum dominant effects. Several residues are found
to tune the excitation by both differentially stabilizing ground and
excited states and through nonclassical “inductive resonance”
interactions. The results obtained with such a quantum-in-classical
model are validated against both experimental data and fully quantum
calculations.