Accurately predicting the protein thermostability changes upon single point mutations in silico is a challenge that has implications for understanding diseases as well as industrial applications of protein engineering. Free energy perturbation (FEP) has been applied to predict the effect of single point mutations on protein stability for over 40 years and emerged as a potentially reliable prediction method with reasonable throughput. However, applications of FEP in protein stability calculations in industrial settings have been hindered by a number of limitations, including the inability to model mutations to and from prolines in which the bonded topology of the backbone is modified and the complexity in modeling charge-changing mutations. In this study, we have extended the FEP+ protocol to enable the accurate modeling of the effects on protein stability from proline mutations and from charge-changing mutations. We also evaluated the influence of the unfolded model in the stability calculations using increasingly longer peptides with native sequence and conformations. With the abovementioned improvements, the accuracy of FEP predictions of protein stability over a data set of 87 mutations on five different proteins has drastically improved compared with previous studies, with a mean unsigned error of 0.86 kcal/mol and root mean square error of 1.11 kcal/mol, comparable with the accuracy of previously published state-of-the-art small-molecule relative binding affinity calculations, which have been shown to be capable of driving discovery projects.