The utility of halogenation in protein design is investigated by a combination of quantitative atomistic simulations and experiment. Application to insulin is of complementary basic and translational interest. In a singly halogenated aromatic ring, regiospecific inductive effects were predicted to modulate multiple surrounding electrostatic (weakly polar) interactions, thereby amplifying changes in thermodynamic stability. In accordance with the simulations, we demonstrated stabilization of insulin by single halogen atoms at the ortho position of an invariant phenylalanine (2-F-Phe