The analytic generalized Born approximation is an efficient electrostatic m
odel that describes molecules in solution. Here it is modified to permit a
more accurate description of large macromolecules, while its established pe
rformance on small compounds is nearly unaffected. The modified model is al
so adapted to describe molecules with an interior dielectric constant not e
qual to unity. The model is tested by computations of pK shifts for a numbe
r of titratable residues in lysozyme, myoglobin, and bacteriorhodopsin. In
general, except for some deeply buried residues of bacteriorhodopsin, the r
esults show reasonable agreement with both experimental data and calculatio
ns based on numerical solution of the Poisson-Boltzmann equation. A very cl
ose agreement between the two models is obtained in an application to the p
rediction of the pK shifts associated with conformational change. The calcu
lations based on this version of the generalized Born approximation are muc
h faster than finite difference solutions of the Poisson-Boltzmann equation
, which makes the present method useful for a variety of other applications
where computational time is a critical factor. The model may also be integ
rated into molecular dynamics programs to replace explicit solvent simulati
ons which are particularly time-consuming for large molecules.