Fragment-based approximations represent an attractive way to circumvent the nonlinear scaling of computational quantum chemistry (QC), whose floatingpoint cost normally grows like O(N p ) as a function of system size (N ), with exponents ranging from p = 3 for density functional theory (DFT) up to p = 7 or higher for levels of theory that provide thermochemical benchmarks. Fragmentation into N sub separate subsystems, each of size n, reduces that cost to N sub × O(n p ) in a manner that is amenable to distributed computing and which does not require modification to electronic structure codes. Nonlinear growth in N sub with system size can be mitigated by means of distance-or energy-based thresholds. The present work presents a protocol for using fragmentation to compute enthalpy changes and activation * herbert@chemistry.ohio-state.edu barriers for enzyme-catalyzed reactions. Over the past decade, benchmark QM calculations have revealed that enzymatic thermochemistry does not converge until hundreds of atoms are included, which is much larger than the QC region in typical quantum mechanics/ molecular mechanics (QM/MM) calculations. Fragmentation may therefore offer an efficient route to obtain converged thermochemical calculations at benchmark levels of theory for N > 500 atoms, provided that errors associated with the fragmentation approximation can be controlled. The present work demonstrates that these errors can be reduced below the "thermochemical accuracy" threshold of 1 kcal/mol, yet highlights the fact that straightforward comparison of fragment-based approximations to full-system benchmarks (as a means to assess errors) is ill-posed, if the calculations are carried out with vacuum boundary conditions.