       Document 0218
 DOCN  M9460218
 TI    Energy calculations and analysis of HIV-1 protease-inhibitor crystal
       structures.
 DT    9408
 AU    Gustchina A; Sansom C; Prevost M; Richelle J; Wodak SY; Wlodawer A;
       Weber IT; Macromolecular Structure Laboratory, NCI-Frederick Cancer;
       Research and Development Center, MD 21702.
 SO    Protein Eng. 1994 Mar;7(3):309-17. Unique Identifier : AIDSLINE
       MED/94233033
 AB    The interactions between HIV-1 protease and its bound inhibitors have
       been investigated by molecular mechanics calculations and by analysis of
       crystal structures of the complexes in order to determine general rules
       for inhibitor and substrate binding to the protease. Fifteen crystal
       structures of HIV-1 protease with different peptidomimetic inhibitors
       showed conservation of hydrogen bond interactions between the main chain
       C = O and NH groups of the inhibitors and the C = O and NH groups of the
       protease extending from P3 C = O to P3' NH. The mean length of the
       hydrogen bonds between the inhibitor and the flexible flaps and the
       conserved water molecule (2.9 A) is slightly shorter than the mean
       length of hydrogen bonds between the inhibitor and the more rigid active
       site region (3.1 A) of the protease. The two hydrogen bonds between the
       conserved water and P2 and P1' carbonyl oxygen atoms of the inhibitor
       are the shortest and are predicted to be important for the tight binding
       of inhibitors. Molecular mechanics analysis of three crystal structures
       of HIV-1 protease with different inhibitors with independent
       calculations using the programs Discover and Brugel gave an estimate of
       56-68% for the contribution of all the inhibitor main chain atoms to the
       total calculated protease-inhibitor interaction energy. The contribution
       of individual inhibitor residues to the interaction energy was
       calculated using Brugel. The main chain atoms of residue P2 had a
       consistently large favorable contribution to the total interaction
       energy, probably due to the presence of the two short hydrogen bonds to
       the flexible flap.(ABSTRACT TRUNCATED AT 250 WORDS)
 DE    Amino Acid Sequence  Chemistry, Physical  Crystallization  Hydrogen
       Bonding  HIV Protease/*CHEMISTRY/METABOLISM  HIV Protease
       Inhibitors/*CHEMISTRY/METABOLISM  HIV-1/*ENZYMOLOGY  Models, Molecular
       Molecular Sequence Data  Support, U.S. Gov't, P.H.S.  Thermodynamics
       JOURNAL ARTICLE

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

