What axe the dielectric "constants" of proteins and how to validate electrostatic models?

Implicit models for evaluation of electrostatic energies in proteins includ e dielectric constants that represent effect of the protein environment. Un fortunately, the results obtained by such models are very sensitive to the value used for the dielectric constant. Furthermore, the factors that deter mine the optimal value of these constants are far from being obvious. This review considers the meaning of the protein dielectric constants and the wa ys to determine their optimal values. It is pointed out that typical benchm arks for validation of electrostatic models cannot discriminate between con sistent and inconsistent models. In particular, the observed pK(a) values o f surface groups can be reproduced correctly by models with entirely incorr ect physical features. Thus, we introduce a discriminative benchmark that o nly includes residues whose pK(a) values are shifted significantly from the ir values in water. We also use the semimacroscopic version of the protein dipole Langevin dipole (PDLD/S) formulation to generate a series of models that move gradually from microscopic to fully macroscopic models. These inc lude the linear response version of the PDLD/S models, Poisson Boltzmann (P B)-type models, and Tanford Kirkwwod (TK)-type models. Using our different models and the discriminative benchmark, we show that the protein dielectri c constant, epsilon (p), is not a universal constant but simply a parameter that depends on the model used. It is also shown in agreement with our pre vious works that epsilon (p) represents the factors that are not considered explicitly. The use of a discriminative benchmark appears to help not only in identifying nonphysical models but also in analyzing effects that are n ot reproduced in an accurate way by consistent models. These include the ef fect of water penetration and the effect of the protein reorganization. Fin ally, we show that the optimal dielectric constant for self-energies is not the optimal constant for charge-charge interactions. Proteins 2001; 44:400 -417. (C) 2001 Wiley-Liss,Inc.