The generalized Born model (GB) provides a reasonably accurate and computationally efficient way to compute the electrostatic component (ΔGel) of the solvation free energy. In this work, we have developed a method to compute effective Born radii, which is intended to address the known secondary structure bias of the GB model reported earlier (Roe et al. J. Phys. Chem. B, 2007, 111, 1846−1857). Our analytical approach, termed AR6, is based on the |r|−6 (R6) integration over an approximation to molecular volume. Within the approach, several computationally efficient corrections to the pairwise VDW−volume integration are combined to closely approximate the true molecular volume in the vicinity of each atom. The accuracy of the AR6 model in predicting relative ΔGel is tested on four conformational states of alanine decapeptide. Changes in ΔGel estimated by AR6 between various pairs of conformational states have the same RMS error relative to the explicit solvent, as do the corresponding numerical PB values; a...