Harmonic-to-anharmonic thermodynamic integration made simple using REG TI

Abstract

Standard harmonic-to-anharmonic thermodynamic integration (TI) is known to develop a near singularity in the integrand for solids exhibiting diffusive degrees of freedom, such as rotating functional groups or migrating defects. This pathology results in numerical challenges for estimating absolute free energies within a single thermodynamic cycle. In this work, we introduce a simple regularization that removes this singularity and yields a well-behaved integrand that can be accurately evaluated on a uniform grid. The approach—termed Regularized End point Gradient (REG) TI—is demonstrated on a model system and on predicting the relative stability of paracetamol polymorphs for which quasi-free methyl rotations lead to a near singularity in standard TI. We expect REG TI to simplify anharmonic free energy calculations for solids and to potentially enable their automation.