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

Sheenam Khuttan; Emilio Gallicchio

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arXiv · 2310.14350

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

Sheenam Khuttan·Emilio Gallicchio

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Abstract

We introduce the self-Relative Binding Free Energy (self-RBFE) approach to evaluate the intrinsic statistical variance of dual-topology alchemical binding free energy estimators. The self-RBFE is the relative binding free energy between 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, the self-RBFE value produced by a finite-length simulation fluctuates and can be used to measure the variance of the model. The results of this validation provide evidence that a significant fraction of the errors observed in benchmark studies reflect the statistical fluctuations of unconverged estimates rather than the models' accuracy. Furthermore, we find that ligand reorganization is a significant contributing factor to the statistical variance of binding free energy estimates and that metadynamics-accelerated conformational sampling of torsional degrees of freedom of the ligand can drastically reduce the time to convergence.

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Sheenam Khuttan, Emilio Gallicchio. 2023-10-22. What to Make of Zero: Resolving the Statistical Noise from Conformational Reorganization in Alchemical Binding Free Energy Estimates with Metadynamics Sampling. https://arxiv.org/abs/2310.14350

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