When designing a mutagenesis experiment, it is often crucial to estimate the stability change of proteins induced by mutations (Delta DG). Despite the recent advances in computational methods, it is still challenging to estimate D DG quickly and accurately. We recently developed the Eris protocols for in silico evaluation of the Delta DG. Starting from the tertiary structure of the wide-type protein, the Eris protocols can model the structure of the mutant protein and estimate Delta DG using the structure models. The Eris protocols not only efficiently optimize the side chains conformations, taking advantage of a fast rotamer-based searching algorithm, but also allow protein backbone flexibility during the modeling. As a result, the Eris protocols effectively resolve steric clashes induced by certain mutations and have more accurate Delta DG predictions than a fixed-backbone approach. We discuss the general aspects of computational Delta DG estimations and discuss in detail the principles and methodologies of the Eris protocols.