Convergence criteria for single-step free-energy calculations: the relation between the Π bias measure and the sample variance

Abstract

Free energy calculations play a crucial role in simulating chemical processes, enzymatic reactions, and drug design. However, assessing the reliability and convergence of these calculations remains a challenge. This study focuses on single-step free-energy calculations using thermodynamic perturbation. It explores how the sample distributions influence the estimated results and evaluates the reliability of various convergence criteria, including Kofke's bias measure Π and the standard deviation of the energy difference ΔU, σ_ΔU. The findings reveal that for Gaussian distributions, there is a straightforward relationship between Π and σ_ΔU, free energies can be accurately approximated using a second-order cumulant expansion, and reliable results are attainable for σ_ΔU up to 25 kcal mol⁻¹. However, interpreting non-Gaussian distributions is more complex. If the distribution is skewed towards more positive values than a Gaussian, converging the free energy becomes easier, rendering standard convergence criteria overly stringent. Conversely, distributions that are skewed towards more negative values than a Gaussian present greater challenges in achieving convergence, making standard criteria unreliable. We propose a practical approach to assess the convergence of estimated free energies.