General Quantum Alchemical Free Energy Simulations via Hamiltonian Interpolation
Abstract
We present an implementation of alchemical free energy simulations at the quantum mechanical level by directly interpolating the electronic Hamiltonian. The method is compatible with any level of electronic structure theory and requires only one quantum calculation for each molecular dynamics step in contrast to multiple energy evaluations that would be needed when interpolating the ground-state energies. We demonstrate the correctness and applicability of the technique by computing alchemical free energy changes of gas-phase molecules, with both nuclear and electron creation/annihilation. We also show an initial application to first-principles pKa calculation for solvated molecules where we quantum mechanically annihilate a bonded proton.
Copyright and License
© 2025 American Chemical Society.
Acknowledgement
This work was primarily supported by the US Department of Energy, Office of Science, Basic Energy Sciences, through Award No. DE-SC0023318. G.K.C. acknowledges additional support in the conceptualization phase from the Dreyfus Foundation, under the program Machine Learning in the Chemical Sciences and Engineering, and from the Simons Investigator program.
Conflict of Interest
The authors declare the following competing financial interest(s): G.K.C. is a part owner of QSimulate Inc. The remaining author declares no competing interests.
Data Availability
Data that support this paper can be found in https://github.com/MoleOrbitalHybridAnalyst/qm_ti_archive.
Additional details
Related works
- Is new version of
- Discussion Paper: arXiv:2408.17002 (arXiv)
- Is supplemented by
- Dataset: https://github.com/MoleOrbitalHybridAnalyst/qm_ti_archive (URL)
Funding
- United States Department of Energy
- DE-SC0023318
- Camille and Henry Dreyfus Foundation
- Simons Foundation
Caltech Custom Metadata
- Caltech groups
- Division of Chemistry and Chemical Engineering (CCE)
- Publication Status
- Published