In eq 8, C V (T ) is the temperature-dependent constant volume heat capacity, N is the total number of replicas, and ∆S is the constant entropy increase (CEI) across all states. Key metrics for assessing the sampling efficiency of replica exchange simulations include the number of transits between the lowest and highest temperatures over a given time period, and the transition matrix of acceptance probabilities. The replica exchange simulations in cg_openmm are executed using the GPU-accelerated openmmtools multistate framework in the canonical ensemble. Even for the small systems considered here, we have found that GPU acceleration provides a dramatic speedup compared to running in parallel with 1 CPU/replica. In this work, 12 replicas were used in all cases, spanning a reduced temperature range of 200