Effective approach for calculations of absolute stability of proteins using focused dielectric constants

The ability to predict the absolute stability of proteins based on their corresponding sequence and structure is a problem of great fundamental and practical importance. In this work, we report an extensive, refinement and validation of our recent approach (Roca et al., FEBS Lett 2007;581:2065-2071) for predicting absolute values of protein stability DeltaG(fold). This approach employs the semimacroscopic protein dipole Langevin dipole method in its linear response approximation version (PDLD/S-LRA) while using the best fitted values of the dielectric constants epsilon'(p) and epsilon'(eff) for the self energy and charge-charge interactions, respectively. The method is validated on a diverse set of 45 proteins. It is found that the best fitted values of both dielectric constants are around 40. However, the self energy of internal residues and the charge-charge interactions of Lys have to be treated with care, using a somewhat lower values of epsilon'(p) and epsilon'(eff). The predictions of DeltaG(fold) reported here, have an average error of only 1.8 kcal/mole compared to the observed values, making our method very promising for estimating protein stability. It also provides valuable insight into the complex electrostatic phenomena taking place in folded proteins.