Consistent description of the effect of internal water in proteins has been a major challenge for both simulation and experimental studies. Describing this effect has been particularly important and elusive in cases of charges in protein interiors. Here, we present a new microscopic method that provides an efficient way for simulating the energetics of water insertion. Instead of performing explicit Monte Carlo (MC) moves on the insertion process, which generally involves an enormous number of rejected attempts, our method is based on generating trial configurations with excess amount of internal water, estimating the relevant free energy by the linear response approximation, and then using a postprocessing MC treatment to filter out a limited number of configurations from a large possible set. Our approach is validated on particularly challenging test cases including the pKa of the V66D mutation in Staphylococcal nuclease, Glu286 in cytochrome c oxidase (CcO) and the energetics of a protonated water molecule in the D channel of CcO. The new postprocessing method allows us to reproduce the relevant energetics of highly unstable charges in protein interiors using fully microscopic calculations and provides a substantial improvement over regular microscopic free energy estimates. This advance established the effectiveness of our water insertion strategy in challenging cases that have not been addressed successfully by other microscopic methods. Furthermore, our study provides a new exciting view on the crucial effect of water penetration in key biological systems as well as a new view on the nature of the dielectric in protein interiors. Proteins 2013. © 2012 Wiley Periodicals, Inc.