  Charge hydration asymmetry (CHA)--a characteristic dependence of hydration
free energy on the sign of the solute charge--quantifies the asymmetric
response of water to electric field at microscopic level. Accurate estimates of
CHA are critical for understanding hydration effects ubiquitous in chemistry
and biology. However, measuring hydration energies of charged species is
fraught with significant difficulties, which lead to unacceptably large (up to
300%) variation in the available estimates of the CHA effect. We circumvent
these difficulties by developing a framework which allows us to extract and
accurately estimate the intrinsic propensity of water to exhibit CHA from
accurate experimental hydration free energies of neutral polar molecules.
Specifically, from a set of 504 small molecules we identify two pairs that are
analogous, with respect to CHA, to the K+/F- pair--a classical probe for the
effect. We use these "CHA-conjugate" molecule pairs to quantify the intrinsic
charge-asymmetric response of water to the microscopic charge perturbations:
the asymmetry of the response is strong, ~50% of the average hydration free
energy of these molecules. The ability of widely used classical water models to
predict hydration energies of small molecules correlates with their ability to
predict CHA.
