A Method for Efficient Calculation of Thermal Stability of Protein upon Point Mutations

Accurate prediction of relative free energy of a protein is of significant importance in protein/enzyme design. A method for efficient prediction of the relative stability of a protein due to single amino acid point mutation is presented. In this approach, one calculates the free energy change due to an arbitrary point mutation of a protein from a single MD trajectory of the wild type protein. The method is tested on 27 diverse protein systems with a total of 853 mutations and the calculated relative free energies show a generally good correlation with experimental values (the correlation coefficient of 0.63). Comparison with the free energy perturbation (FEP) method and recently developed machine learning methods on two different benchmark data sets show that the current method is computationally efficient and also numerically reliable for predicting the changes of thermostability upon an arbitrarily point mutation of a protein. Discussion is provided on how to further improve the accuracy of the method for prediction of thermostability of protein.