Efficient Multistate Free-Energy Calculations with QM/MM Accuracy Using Replica-Exchange Enveloping Distribution Sampling

2025/06/06 by Domen Pregeljc, Ramon J. R. Hügli, Sereina Riniker · 1 voice · 1 citation
Engineering · Physics and Astronomy · #Nuclear reactor physics and engineering #Quantum and electron transport phenomena #Theoretical and Computational Physics

paper · pdf · doi:10.1021/acs.jpcb.5c02086

openalex publication_date 2025/06/06 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/10

Abstract

Calculating free-energy differences using molecular dynamics (MD) simulations is an important task in computational chemistry. In practice, the accuracy of the results is limited by model approximations and insufficient phase-space sampling due to limited computational resources. In the present work, we address these challenges by integrating the quantum-mechanical/molecular-mechanical (QM/MM) scheme with replica-exchange enveloping distribution sampling (RE-EDS) to obtain a multistate and multiscale free-energy method with high computational efficiency. The performance of QM/MM RE-EDS is showcased by calculating hydration free energies for three data sets using semiempirical methods for the QM zone. We highlight the importance of the choice of QM Hamiltonian and the effect of the compatibility between the QM and MM models. Especially the choice of semiempirical method has a substantial effect on the accuracy compared to experiment, but also the choice of MM water model is non-negligible. Our findings indicate that RE-EDS is an efficient approach for calculating free-energy differences with a QM/MM scheme, and lays the foundation for future developments and applications.

Citations

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Discussions

• Our newest publication explores using QM/MM together with RE-EDS to do efficient free-energy calculations, enabling increased accuracy and allowing highly polarized systems to be studied. #chemsky #co [bsky, 9 points, 0 comments]

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