FEPCert: An Open-Source Toolkit for Quality-Control, Phase Space Overlap, and Thermodynamic Cycle Closure Certification of Alchemical Free Energy Simulations

Abstract

FEPCert checks alchemical free-energy calculations and perturbation networks: thermodynamic integration (including paths in which several lambda components change) and BAR, the two-state MBAR overlap of neighbouring states, the agreement of TI with BAR on the same states (quadrature error), time convergence, and the closure of thermodynamic cycles with z-scores against the edge uncertainties. It reads GROMACS dhdl.xvg files, including the energy differences to the other states, or tables, and reports PASS, WARNING, FAIL or NOT_APPLICABLE for each check. Version 1.2.0 was validated on 28 analyses of real GROMACS data (alchemtest: benzene and ethanol hydration, a protein-ligand absolute binding free energy in T4 lysozyme and a water particle, with full, truncated and thinned lambda schedules) against alchemlyb and pymbar, and on the 92 perturbation maps of the public FEP+ benchmark against networkx. It corrects defects of 1.1.0 found by that validation: the overlap was computed from histograms of dH/dlambda and did not measure phase-space overlap; the cycle enumeration missed 104 of 1404 cycles; thresholds ignored the energy unit. Validation scripts and results are in the validation/ directory of the GitHub release.