Document 0094
 DOCN  M9550094
 TI    Relative binding free energies of peptide inhibitors of HIV-1 protease:
       the influence of the active site protonation state.
 DT    9505
 AU    Chen X; Tropsha A; Laboratory for Molecular Modeling, School of
       Pharmacy, University; of North Carolina, Chapel Hill 27599.
 SO    J Med Chem. 1995 Jan 6;38(1):42-8. Unique Identifier : AIDSLINE
       MED/95139034
 AB    Hydrogen bonding plays an important role in the stabilization of
       complexes between HIV-1 protease (HIV-1 PR) and its inhibitors. The
       adequate treatment of the protease active site protonation state is
       important for accurate molecular simulations of the protonation state is
       important for accurate molecular simulations of the protease-inhibitor
       complexes. We have applied the free energy simulation/thermodynamic
       cycle approach to evaluate the relative binding affinities of the S vs R
       isomers of the U85548E inhibitor of the protease. Several mono- and
       diprotonation states of the catalytic aspartic acid residues of the
       protease active site were considered in the course of molecular
       simulations. The calculated difference in binding free energy of the S
       vs R isomers strongly depended on the location of proton(s), but in all
       cases the binding free energy of the S inhibitor was higher. On the
       basis of our calculations, we propose that in the HIV-1 PR-inhibitor
       complex only one catalytic aspartic acid residue is protonated and that
       the binding free energy of the S isomer is ca. 2.8 kcal/mol higher than
       that of the R isomer. The accuracy of these predictions shall be
       evaluated when binding affinities of both isomers become available.
 DE    Amino Acid Sequence  Aspartic Acid/METABOLISM  Binding Sites
       Comparative Study  Energy Transfer  HIV Protease/*CHEMISTRY/*METABOLISM
       HIV Protease Inhibitors/*CHEMISTRY  Models, Chemical  Molecular Sequence
       Data  Oligopeptides/CHEMISTRY/METABOLISM
       Peptides/*CHEMISTRY/*METABOLISM  Protein Binding  Protons  Solutions
       Stereoisomers  Support, Non-U.S. Gov't  Thermodynamics  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).