Two mechanisms have been proposed to drive asymmetric solvent response to a so-
lute charge: a static potential contribution similar to the liquid-vapor potential, and
a steric contribution associated with a water molecule.s structure and charge dis-
tribution. In this work, we use free-energy perturbation (FEP) molecular-dynamics
(MD) calculations in explicit water to show that these mechanisms act in comple-
mentary regimes; the large static potential ( 44 kJ/mol/e) dominates asymmetric
response for deeply buried charges, and the steric contribution dominates for charges
near the solute.solvent interface. Therefore, both mechanisms must be included in
order to fully account for asymmetric solvation in general. Our calculations suggest
that the steric contribution leads to a remarkable deviation from the popular .linear
response. model in which the reaction potential changes linearly as a function of
charge. In fact, the potential varies in a piecewise-linear fashion, i.e. with different
proportionality constants depending on the sign of the charge. This discrepancy is
significant even when the charge is completely buried, and holds for solutes larger
than single atoms. Together, these mechanisms suggest that implicit-solvent models
can be improved using a combination of affine response (an offset due to the static
potential) and piecewise-linear response (due to the steric contribution).