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

被引:113
作者
WALLQVIST, A
JERNIGAN, RL
COVELL, DG
机构
[1] NCI, SCI APPLICAT INT CORP, FREDERICK CANC RES & DEV CTR, FREDERICK, MD 21702 USA
[2] NCI, MATH BIOL LAB, BETHESDA, MD 20892 USA
关键词
ATOM-ATOM INTERACTIONS; BINDING; MOLECULAR SURFACE; PROTEIN; RECOGNITION;
D O I
10.1002/pro.5560040923
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:1881 / 1903
页数:23
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