The disclosure provides methods for designing and producing mutants that stabilize a protein. The folding energy of the protein and various mutants can be determined based on an equation comprising intrinsic pKa, of the amino acids, the pH, charge of the amino acids, distances between the amino acids, an optimized dielectric constant for self-energy (∈′p) or an optimized dielectric constant for charge-charge interaction (∈′eff) and compared. A more negative folding energy of the mutant indicates a more stable protein. When a stable mutant is identified, it can be produced with technologies such as cloning and expression.