Abstract
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.