(589g) Calculations of Absolute Stability of Proteins, Using Molecular Dynamics and 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(10):2065-2071) for predicting absolute values of protein stability ΔG_fold. This approach employs the semimacroscopic protein dipole Langevin dipole method in its linear response approximation version (PDLD/S-LRA) while using optimal values of dielectric constants ε_p and ε_eff. The method is optimized and validated on a diverse set of 45 proteins. It is found that optimal 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 ε_p and ε_eff. The predictions of ΔG_fold reported here, have an average error of only 1.8 kcal/mole compared to the observed values, making this method very promising for estimating protein stability. The ability of this method to predict mutations that can stabilize a protein is also investigated. This work provides valuable insight into the complex electrostatic phenomena taking place in folded proteins.