On average, the calculations using the TPSS functional and D3 dispersion correction appear to overbind the crystal between 3.90-5.24 kJ/mol compared to the experimentally-derived results. This propensity to overbind is marginally greater for hydrogen bonding structures (4.70-6.94 kJ/mol) compared to non-hydrogen bonding structures (3.47-4.30 kJ/mol). The largest deviations in energies are observed for the crystal structure of melamine (MELAMI06) and quinolin-8-ol (HXQUIN14), both of which are hydrogen bonding. For MELAMI06, the two available experimental datapoints suggest that DFT-D overbinds the crystal by 20.46 kJ/mol and 25.98 kJ/mol . The sublimation enthalpy data obtained from was determined at an elevated temperature of 432 K, which one could potentially point to as a source of large errors when the temperature correction is applied. However, the enthalpy data obtained from was determined at 298.15 K, making the temperature-correction argument less valid at explaining the calculated overbinding. Furthermore, if the reported experimental measurement error for this source (±4 kJ/mol) is taken into consideration, both sources are actually in good agreement that the DFT-D calculated lattice energy for MELAMI06 may be too negative. For HXQUIN14, there are five different experimental measurements quoted , all obtained at 298.15 K. The five measurements can be split into two groups: two measurements with reported experimental sublimation enthalpies within 0.2 kJ/mol of each other, and three measurements with reported experimental sublimation enthalpies within 1.6 kJ/mol of each other. The average sublimation enthalpies of these two The intermolecular energy used as reference data in the parameter estimation is determined by removal of the intramolecular cost of deforming the molecule from its in vacuo conformation from the overall lattice energy. As structures are preferentially selected to include mostly rigid molecules, we expect the intramolecular contributions to lattice energy to be small for most structures. For the nonhydrogen bonding structures in our reference datasets, the intramolecular component of the lattice energy is predicted to be 1.77 kJ/mol on average, within the range of 0.08-9.94 kJ/mol. In these structures, the differences in intramolecular energy usually correspond to small changes in the equilibrium geometry of the molecule as the molecular structure is strained by intermolecular packing forces. In other cases, large intramolecular contributions can be due to the chosen molecules exhibiting varying degrees of flexibility. While this contradicts our intention of using rigid molecules, it is sometimes unavoidable since certain atomic environments are inherently found in flexible molecules. On the other hand, the average intramolecular energy for the hydrogen bonding structures is much larger at 10.79 kJ/mol, with a range of 0.50-38.90 kJ/mol. Like the non-hydrogen bonding structures, most of the hydrogen bonding molecules do not exhibit significant changes between the crystalline environment and the gas phase. Despite this, a large intramolecular energy penalty is still incurred, suggesting that the observed molecular adjustments are highly destabilising and are only tenable in the context of promoting intermolecular hydrogen bond formation. For example, acetic acid has a predicted intramolecular energy contribution of 12.0 kJ/mol despite very small differences in the conformation of the molecule between its optimal gaseous and crystalline state, as reflected by the small RMSD 1 value of 0.018 Å. The largest change is for the hydrogen atom position in the O-H bond. In the crystalline state, the O-H bond length is extended by approximately 5% from 0.96 Å to 1.03 Å with a slight increase in the C-O-H bond angle. This perturbation leads to large energetic costs when not surrounded by the highly polarising environment of a hydrogen bond, but in the crystal it allows the acetic acid molecule to take advantage of intermolecular hydrogen bonds with its neighbours. In more extreme cases, the conformational adjustment can even be at the expense of an existing intramolecular hydrogen bond. For instance, nicotinohydroxamic acid (FUZZAB) has the largest predicted intramolecular energy contribution (38.90 kJ/mol). If only the heavy elements of the molecule are considered, the RMSD 1 between the equilibrium and crystal phase conformation is 0.098 Å, which when the two conformations are overlaid is rather minor (Figure ). In the equilibrium conformation, the hydrogen connected to the oxygen in the acid group is orientated in the same plane as the nearby carbonyl oxygen, facilitating strong intramolecular hydrogen bond formation.