Crystal energy differences can be calculated but they cannot be directly measured because the enthalpy difference that is measured includes a contribution from differences in the zero point and thermal vibrational energies. This is usually insignificant unless hydrogen bonds are involved. This is because hydrogen bonding has a large effect on frequencies, Different patterns of hydrogen bonding in two different crystal structures can give rise to a ¿vibrational energy difference¿ that is larger than their lattice energy difference. This makes it hard to test computational methods for their accuracy. Having a reliable computational method for crystal lattice energies is a prerequisite for being able to compute the relative energy of two crystal forms or for simulations of the energy of binding of small molecules to macromolecules as in enzyme inhibitor complexes.