The second challenge is related to force field parametrization itself. If a molecule of interest (modified biological residue, substrate or other ligand, etc.) does not exist as a predefined entity in the force field, the user must develop parameters for it. Doing so often requires knowledge of QM calculations, parameter fitting approaches, and validation against empirical data. Given the intense nature of these tasks, automated methods have been developed to assist users in parametrizing species of interest. Despite the availability of such tools, a major challenge remains in validating the resulting topology. Many users do not scrutinize the suitability of the topology and assigned parameters, instead relying on a "black box" acceptance of the automated methods. Where scoring functions exist to indicate topological quality, these should be used to the greatest extent possible. It should be understood that parametrizing a new species is a major undertaking that requires deep theoretical and practical knowledge, rather than a trivial task that can be achieved in little time.