Conformational sampling is restrained in most successful refinement methods in order to prevent large-scale unfolding and focus sampling on reaching the native state. Unrestrained MD simulations from protein models usually result in a significant deterioration of model qualities, at least over the time scales that can be reached via simulations today. The force field used in the simulations may have deficits that drive the simulated models towards the unfolded state, or, more likely, there are simply unfavorable contacts in the initial models that lead to rapid unfolding in order to reach a conformation with more favorable interactions. Once unfolded, there is not enough time to refold to the native state. Under the assumption that the native state is indeed the most favorable state based on free energies, restraints are applied to prevent unfolding so that sampling can find the native state more quickly. However, there is a compromise between the application of restraints and the need for conformational transitions since some degree of unfolding may be crucial for the refinement of structural defects in the initial model . Other reasons for applying restraints to an initial conformation is that simulations of a monomeric apo structure may neglect important stabilizing interactions due to oligomerization, ligand binding, or other biomolecular interactions in the physiological environment. During structure prediction, such factors could be transferred implicitly from known structures via restraints.