A structural thermodynamic approach to the design of aspartic protease inhibitors is proposed. The energy of binding of small peptides is now well characterized. This information may be used in the rational design of peptidomimetic inhibitors of medically relevant aspartic proteases such as HIV protease. This work involves the use of structural thermodynamic algorithms developed at the center used in conjunction with docking algorithms in order to design peptides that are predicted to have the highest affinity for the protease. These predictions are then compared to experimental binding data obtained on the center calorimeters.