Intermediate Thermodynamic States Contribute Equally to Free Energy Convergence: A Demonstration with Replica Exchange

We investigate the relationship between the number of intermediate thermodynamic states along a pathway and the precision of free energy estimates. With a sufficient number of states, the asymptotic variance collapses as a function of the total sample size. Our analytical result is corroborated by replica exchange molecular dynamics simulations of model systems in which the neighbor exchange rate exceeds 35%. Precision collapse is also observed in heat capacity estimates based on the multistate Bennett acceptance ratio. In contrast to the relaxation and mean first-passage times, the autocorrelation time of state indices is found to be relevant to free energy convergence.