which is the loss function mentioned in the Introduction. This formulation has been originally developed for the EROS method 8 based on a method for image reconstruction. Since then it has entered into the BME method , for example. Note that any method that is equivalent to refinement by replica simulations is also equivalent to the EROS/BioEn method with properly chosen coupling constant and in the limit of infinite numbers of replicas. As discussed in Ref. 9, the dependence on the number of replicas can be removed with a subsequent BioEn refinement.