FoldX is an empirical force field for the rapid calculation of mutational free energies in proteins and nucleic acids which relies directly on structure-activity data from protein-engineering experiments to calculate interaction energies. The advantage of using an empirical force field is multiple: First, FoldX is perfectly geared to the simulation of biological macromolecules, as the calibration data and simulated model systems are on a similar scale of complexity. Secondly, as FoldX relies on structure-activity information, it provides a rationale for the physical interpretation of changes in free energy. Finally, the FoldX force-field was primarily designed to allow fast and accurate estimations of free energy changes upon mutation in proteins or protein complexes. FoldX has similar accuracy as physical force fields for prediction of free energy changes, yet it is many orders of magnitude faster, as the estimation of entropic contributions to protein interactions is directly derived from the structure using a statistical thermodynamics approach. As such FoldX provides a powerful tool for high-throughput structure-activity analyses of proteomes, prediction of protein folding pathways or protein design.
Initialy developed by Luis Serrano at EMBL Heidelberg, since several years the effort of continued improvement of the force field as well as the creation of novel applications for protein design and homology modelling is shared between the Serrano Lab at CRG Barcelona and the VIB Switch Laboratory in Brussels. The main fields in which applications of the FoldX force field are being persued are homology modelling, protein dynamics and protein-protein interactions.