# Targeted Free Energy Perturbation

Ranking polymorphs of molecular crystals by thermodynamic stability has relied on the Einstein crystal method (ECM), which must sample a separate chain of overlapping alchemical states for every polymorph, a cost that grows unmanageable across large crystal landscapes. This work hands the mapping in targeted free-energy perturbation to a normalizing flow: the model reversibly transforms molecular-dynamics supercell configurations onto an analytical reference distribution, and targeted Bennett acceptance ratio (tBAR) reweighting then yields lattice free energies. On succinic acid, Veliparib and Mivebresib the estimates agree with ECM, handle supercells of up to about 3×10³ degrees of freedom, and take on average roughly one over 2.5 of the ECM time.

Ranking polymorphs of molecular crystals by thermodynamic stability has relied on the Einstein crystal method (ECM), which must sample a separate chain of overlapping alchemical states for every polymorph, a cost that grows unmanageable across large crystal landscapes. This work hands the mapping in targeted free-energy perturbation to a normalizing flow: the model reversibly transforms molecular-dynamics supercell configurations onto an analytical reference distribution, and targeted Bennett acceptance ratio (tBAR) reweighting then yields lattice free energies. On succinic acid, Veliparib and Mivebresib the estimates agree with ECM, handle supercells of up to about 3×10³ degrees of freedom, and take on average roughly one over 2.5 of the ECM time.