A new method that incorporates the conductorlike polarizable continuum model ͑CPCM͒ with the recently developed molecular fractionation with conjugate caps ͑MFCC͒ approach is developed for ab initio calculation of electrostatic solvation energy of protein. The application of the MFCC method makes it practical to apply CPCM to calculate electrostatic solvation energy of protein or other macromolecules in solution. In this MFCC-CPCM method, calculation of protein solvation is divided into

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... ions of individual solvation energies of fragments ͑residues͒ embedded in a common cavity defined with respect to the entire protein. Besides computational efficiency, the current approach also provides additional information about contribution to protein solvation from specific fragments. Numerical studies are carried out to calculate solvation energies for a variety of peptides including ␣ helices and ␤ sheets. Excellent agreement between the MFCC-CPCM result and those from the standard full system CPCM calculation is obtained. Finally, the MFCC-CPCM calculation is applied to several real proteins and the results are compared to classical molecular mechanics Poisson-Boltzmann ͑MM/PB͒ and quantum Divid-and-Conque Poisson-Boltzmann ͑D&C-PB͒ calculations. Large wave function distortion energy ͑solute polarization energy͒ is obtained from the quantum calculation which is missing in the classical calculation. The present study demonstrates that the MFCC-CPCM method is readily applicable to studying solvation of proteins.