Funnel metadynamics as accurate binding free-energy method

A detailed description of the events ruling ligand/protein interac- tion and an accurate estimation of the drug affinity to its target is of great help in speeding drug discovery strategies. We have de- veloped a metadynamics-based approach, named funnel metady- namics, that allows the ligand to enhance the sampling of the target binding sites and its solvated states. This method leads to an effi- cient characterization of the binding free-energy surface and an accurate calculation of the absolute protein–ligand binding free energy. We illustrate our protocol in two systems, benzamidine/ trypsin and SC-558/cyclooxygenase 2. In both cases, the X-ray con- formation has been found as the lowest free-energy pose, and the computed protein–ligand binding free energy in good agreement with experiments. Furthermore, funnel metadynamics unveils im- portant information about the binding process, such as the presence of alternative binding modes and the role of waters. The results achieved at an affordable computational cost make funnel meta- dynamics a valuable method for drug discovery and for dealing with a variety of problems in chemistry, physics, and material science.