When designing a mutagenesis experiment, it is often crucial to estimate the stability change of proteins induced by mutations (δδG). Despite the recent advances in computational methods, it is still challenging to estimate δ δG quickly and accurately. We recently developed the Eris protocols for in silico evaluation of the δ δG. Starting from the tertiary structure of the wide-type protein, the Eris protocols can model the structure of the mutant protein and estimate δ δG 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 δ δG predictions than a fixed-backbone approach. We discuss the general aspects of computational δ δG estimations and discuss in detail the principles and methodologies of the Eris protocols.