The binding sites of proteins generally contain smaller regions that provide major contributions to the binding free energy and hence are the prime targets in drug design. Screening libraries of fragment-sized compounds by NMR or X-ray crystallography demonstrates that such hot spot regions bind a large variety of small organic molecules, and that a relatively high hit rate is predictive of target sites that are likely to bind drug-like ligands with high affinity. Our goal is to determine the hot spots computationally rather than experimentally.