The MD component of the MC/MD calculations and the pure MD reference simulations used the SHAKE algorithm with the default tolerance of 0.00001 Å. Because these particular calculations were run at 500K, the atomic speeds are large, so the integration time step was set to 0.2 fs to minimize deviations from the Boltzmann ensemble. This maximizes compatibility with the MC steps, for which there are no finite time-step errors. (For the other simulations in this work, the MD time step was 2 fs.) The reference MD simulation was run for 20 ns, and the MD energy was recorded every 10 steps, which resulted in 10 7 energy calculations. The MC/MD calculations alternated runs of 10 MD steps with an MC step with NMC = 10. As our MC/MD method is optimized to work for protein-ligand complexes and small cavities, using our method on a gas-phase system that is composed of mostly cavities is highly inefficient and is therefore considerably slower compared to MD. However, we think it is the most accurate way to examine the thermodynamic character of the system. We ran eight MC/MD calculations, each with 1.25 × 10 6 cycles, for a total of 10 7 energy calculations. All MC/MD and MD runs started with the same initial configuration of the equilibrated gas but used different random number seeds.