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We introduce the self-Relative Binding Free Energy (self-RBFE) approach toevaluate the intrinsic statistical variance of dual-topology alchemical bindingfree energy estimators. The self-RBFE is the relative binding free energybetween a ligand and a copy of the same ligand, and its true value is zero.Nevertheless, because the two copies of the ligand move independently, theself-RBFE value produced by a finite-length simulation fluctuates and can beused to measure the variance of the model. The results of this validationprovide evidence that a significant fraction of the errors observed inbenchmark studies reflect the statistical fluctuations of unconverged estimatesrather than the models' accuracy. Furthermore, we find that ligandreorganization is a significant contributing factor to the statistical varianceof binding free energy estimates and that metadynamics-acceleratedconformational sampling of torsional degrees of freedom of the ligand candrastically reduce the time to convergence.

What to Make of Zero: Resolving the Statistical Noise from  Conformational Reorganization in Alchemical Binding Free Energy Estimates  with Metadynamics Sampling