Validation of free energy methods in AMBER

Hsu Chun Tsai, Yujun Tao, Tai Sung Lee, Kenneth M. Merz, Darrin M. York

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Herein we provide high-precision validation tests of the latest GPU-accelerated free energy code in AMBER. We demonstrate that consistent free energy results are obtained in both the gas phase and in solution. We first show, in the context of thermodynamic integration (TI), that the results are invariant with respect to "split"(e.g., stepwise decharge-vdW-recharge) versus "unified"protocols. This brought to light a subtle inconsistency in previous versions of AMBER that was traced to the improper treatment of 1-4 vdW and electrostatic interactions involving atoms across the softcore boundary. We illustrate that under the assumption that the ensembles produced by different legs of the alchemical transformation between molecules A and B in the gas phase and aqueous phase are very small, the inconsistency in the relative hydration free energy ΔΔGhydr[A → B] = ΔGaq[A → B] - ΔGgas[A → B] is minimal. However, for general cases where the ensembles are shown to be substantially different, as expected in ligand-protein binding applications, these errors can be large. Finally, we demonstrate that results for relative hydration free energy simulations are independent of TI or multistate Bennett's acceptance ratio (MBAR) analysis, invariant to the specific choice of the softcore region, and in agreement with results derived from absolute hydration free energy values.

Original languageEnglish (US)
Pages (from-to)5296-5300
Number of pages5
JournalJournal of Chemical Information and Modeling
Issue number11
StatePublished - Nov 23 2020

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

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