Despite the reduction in coupling, we note that our protocol is likely to be less efficient than replica-exchange-based methodologies in terms of absolute computing time, especially highly flexible schemes such as ensemble of expanded ensemble. In principle, there is no reason why this algorithm should not be applied in combination with replica exchange methods; for example, windows with low statistical inefficiencies could be run for less time between exchange attempts than windows with high statistical inefficiencies. However, this is more complicated, since the statistical inefficiency at a given λ window becomes a function of the sampling at all other λ windows and the inter-window exchange probabilities, making it less clear where additional sampling time would be best allocated. Alternatively, windows showing large inter-run ∆G deviations could be targeted by enhanced sampling algorithms.