A PREFERENCE-BASED FREE-ENERGY PARAMETERIZATION OF ENZYME-INHIBITOR BINDING - APPLICATIONS TO HIV-1-PROTEASE INHIBITOR DESIGN

The interface between protein receptor-ligand complexes has been studi ed with respect to their binary interatomic interactions. Crystal stru cture data have been used to catalogue surfaces buried by atoms from e ach member of a bound complex and determine a statistical preference f or pairs of amino-acid atoms. A simple free energy model of the recept or-ligand system is constructed from these atom-atom preferences and u sed to assess the energetic importance of interfacial interactions. Th e free energy approximation of binding strength in this model has a re liability of about +/-1.5 kcal/mol, despite limited knowledge of the u nbound states. The main utility of such a scheme lies in the identific ation of important stabilizing atomic interactions across the receptor -ligand interface. Thus, apart from an overall hydrophobic attraction (Young L, Jernigan RL, Covell DG, 1994, Protein Sci 3:717-729), a rich variety of specific interactions is observed. An analysis of 10 HIV-1 protease inhibitor complexes is presented that reveals a common bindi ng motif comprised of energetically important contacts with a rather l imited set of atoms. Design improvements to existing HIV-1 protease in hibitors are explored based on a detailed analysis of this binding mot if.