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We report the development and testing of new integrated cyberinfrastructure for performing free energy simulations with generalized hybrid quantum mechanical/molecular mechanical (QM/MM) and machine learning potentials (MLPs) in Amber. The Sander molecular dynamics program has been extended to leverage fast, density-functional tight-binding models implemented in the DFTB+ and xTB packages, and an interface to the DeePMD-kit software enables the use of MLPs. The software is integrated through application program interfaces that circumvent the need to perform “system calls” and enable the incorporation of long-range Ewald electrostatics into the external software’s self-consistent field procedure. The infrastructure provides access to QM/MM models that may serve as the foundation for QM/MM–ΔMLP potentials, which supplement the semiempirical QM/MM model with a MLP correction trained to reproduce ab initio QM/MM energies and forces. Efficient optimization of minimum free energy pathways is enabled through a new surface-accelerated finite-temperature string method implemented in the FE-ToolKit package. Furthermore, we interfaced Sander with the i-PI software by implementing the socket communication protocol used in the i-PI client–server model. The new interface with i-PI allows for the treatment of nuclear quantum effects with semiempirical QM/MM–ΔMLP models. The modular interoperable software is demonstrated on proton transfer reactions in guanine-thymine mispairs in a B-form deoxyribonucleic acid helix. The current work represents a considerable advance in the development of modular software for performing free energy simulations of chemical reactions that are important in a wide range of applications.
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This content will become publicly available on June 21, 2025
Software Infrastructure for Next-Generation QM/MM−ΔMLP Force Fields
We present software infrastructure for the design and testing of new quantum mechanical/molecular mechanical and machine-learning potential (QM/MM−ΔMLP) force fields for a wide range of applications. The software integrates Amber’s molecular dynamics simulation capabilities with fast, approximate quantum models in the xtb package and machine-learning potential corrections in DeePMD-kit. The xtb package implements the recently developed density-functional tight-binding QM models with multipolar electrostatics and density-dependent dispersion (GFN2-xTB), and the interface with Amber enables their use in periodic boundary QM/MM simulations with linear-scaling QM/MM particle-mesh Ewald electrostatics. The accuracy of the semiempirical models is enhanced by including machine-learning correction potentials (ΔMLPs) enabled through an interface with the DeePMD-kit software. The goal of this paper is to present and validate the implementation of this software infrastructure in molecular dynamics and free energy simulations. The utility of the new infrastructure is demonstrated in proof-of-concept example applications. The software elements presented here are open source and freely available. Their interface provides a powerful enabling technology for the design of new QM/MM−ΔMLP models for studying a wide range of problems, including biomolecular reactivity and protein–ligand binding.
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- Award ID(s):
- 2209718
- PAR ID:
- 10517513
- Publisher / Repository:
- ACS
- Date Published:
- Journal Name:
- The Journal of Physical Chemistry B
- ISSN:
- 1520-6106
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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