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Validation of Free Energy Methods in AMBER
Hsu-Chun Tsai1, Yujun Tao1, Tai-Sung Lee1
1Laboratory for Biomolecular Simulation Research, Center for Integrative Proteomics Research, and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, United States.
Journal of Chemical Information and Modeling
|June 20, 2020
Summary
This study validates GPU-accelerated free energy calculations in AMBER, ensuring consistent results across different phases and protocols. It identifies and corrects an inconsistency in handling specific interactions, improving accuracy for relative hydration free energy calculations.
Area of Science:
- Computational Chemistry
- Molecular Dynamics Simulations
- Free Energy Calculations
Background:
- Accurate free energy calculations are crucial for molecular modeling.
- Previous AMBER versions had inconsistencies in handling specific interactions during alchemical transformations.
- GPU acceleration offers potential for faster and more precise simulations.
Purpose of the Study:
- To validate the latest GPU-accelerated free energy code in AMBER.
- To assess the consistency of free energy results across different protocols and phases.
- To identify and rectify sources of error in free energy calculations, particularly for relative hydration free energies.
Main Methods:
- High-precision validation tests using thermodynamic integration (TI) and multistate Bennett's acceptance ratio (MBAR).
- Comparison of "split" versus "unified" protocols for alchemical transformations.
- Analysis of 1-4 van der Waals (vdW) and electrostatic interactions across softcore boundaries.
- Gas phase and solution simulations for relative hydration free energy calculations.
Main Results:
- Consistent free energy results were achieved using both split and unified protocols.
- A subtle inconsistency in previous AMBER versions related to 1-4 vdW and electrostatic interactions was identified and corrected.
- Errors in relative hydration free energy (ΔΔGhydr) can be substantial when ensembles differ significantly, as in ligand-protein binding.
- Simulation results were independent of TI or MBAR analysis and the choice of softcore region.
Conclusions:
- The latest GPU-accelerated free energy code in AMBER provides reliable and consistent results.
- Proper treatment of 1-4 interactions is critical for accurate free energy calculations, especially in solution.
- The corrected code improves the accuracy of relative hydration free energy predictions, crucial for applications like drug discovery.
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