The relationship between protein sequence and its thermodynamic stability is a critical aspect of computational protein design. In this work, we present a new theoretical method to calculate the free energy change (ΔΔ G ) resulting from a single-point amino acid mutation to alanine in a protein sequence. The method is derived based on physical interactions and is very efficient in estimating the free energy changes caused by a series of alanine mutations from just a single molecular dynamics (MD) trajectory. Numerical calculations are carried out on a total of 547 alanine mutations in 19 diverse proteins whose experimental results are available. The comparison between the experimental ΔΔ G exp and the calculated values shows a generally good correlation with a correlation coefficient of 0.67. Both the advantages and limitations of this method are discussed. This method provides an efficient and valuable tool for protein design and engineering.