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 studied with respect to their binary interatomic interactions. Crystal structure data have been used to catalogue surfaces buried by atoms from each member of a bound complex and determine a statistical preference for pairs of amino-acid atoms. A simple free energy model of the receptor-ligand system is constructed from these atom-atom preferences and used to assess the energetic importance of interfacial interactions. The free energy approximation of binding strength in this model has a reliability of about +/- 1.5 kcal/mol, despite limited knowledge of the unbound states. The main utility of such a scheme lies in the identification 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 binding motif comprised of energetically important contacts with a rather limited set of atoms. Design improvements to existing HIV-1 protease inhibitors are explored based on a detailed analysis of this binding motif.
Wallqvist
A
A
Frederick Cancer Research and Development Center, National Cancer Institute, Frederick, Maryland 21702, USA.
Jernigan
R L
RL
Covell
D G
DG
D000438:Alcohols / Q000737:chemistry; D001665:Binding Sites; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015195:Drug Design; D004563:Electrochemistry; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology*; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013816:Thermodynamics
D000438:Alcohols; D017320:HIV Protease Inhibitors; D013438:Sulfhydryl Compounds; D016333:HIV Protease