Finite-Sample Bias in Free Energy Bridge Estimators

J. Chem. Phys. 151, 034105 (2019)

Authors: B. K. Radak

In practical free energy estimation, the bias is often neglected once it has been shown to vanish in the large-sample limit. Yet finite-sample bias always exists and ought to be considered in any rigorous study. This work develops a metric for bias in a broad class of free energy “bridge estimators” (e.g., Bennett’s method). The framework complements existing variance estimation methods and provides a means for comparing systematic and statistical errors. Examples show that, contrary to what is often assumed, the bias can be quite substantial when the sample size is modest.

The Journal of Chemical Physics