A. Wallqvist et al., A PREFERENCE-BASED FREE-ENERGY PARAMETERIZATION OF ENZYME-INHIBITOR BINDING - APPLICATIONS TO HIV-1-PROTEASE INHIBITOR DESIGN, Protein science, 4(9), 1995, pp. 1881-1903
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.