FoldX force field revisited, an improved version

Abstract

Motivation: The FoldX force field was originally validated with a database of 1000 mutants at a time when there were few high-resolution structures. Here, we have manually curated a database of 5556 mutants affecting protein stability, resulting in 2484 highly confident mutations denominated FoldX stability dataset (FSD), represented in non-redundant X-ray structures with <2.5 Å resolution, not involving duplicates, metals, or prosthetic groups. Using this database, we have created a new version of the FoldX force field by introducing pi stacking, pH dependency for all charged residues, improving aromatic-aromatic interactions, modifying the Ncap contribution and α-helix dipole, recalibrating the side-chain entropy of methionine, adjusting the H-bond parameters, and modifying the solvation contribution of tryptophan and others. Results: These changes have led to significant improvements for the prediction of specific mutants involving the above residues/interactions and a statistically significant increase of FoldX predictions, as well as for the majority of the 20 aa. Removing all training sets data from FSD [Validation FoldX Stability Dataset (VFSD) dataset] resulted in improved predictions from R = 0.693 (RMSE = 1.277 kcal/mol) to R = 0.706 (RMSE = 1.252 kcal/mol) when compared with the previously released version. FoldX achieves 95% accuracy considering an error of ±0.85 kcal/mol in prediction and an area under the curve = 0.78 for the VFSD, predicting the sign of the energy change upon mutation.