Protein Engineering vol. 9 no. 8 pp. 679-690, 1996
© 1996 Oxford University Press
RESEARCH-ARTICLE |
Molecular mechanics calculations on HIV-1 protease with peptide substrates correlate with experimental data
Department of Pharmacology, Jefferson Cancer Center, Thomas Jefferson University Philadelphia, PA 19107, USA
Molecular models of HIV-1 protease and 21 peptide substrates with single amino acid substitutions at positions from P4 to P3' were built and compared with kinetic measurements. The crystal structure of HTV-1 protease with a peptidic inhibitor was modified to model the peptide substrate Pro-Ala-Val-Ser-Leu-Ala-Met-Thr for the starting geometry. Models were built of two reaction intermediates, HIV protease with peptide substrate and with its tetrahedral intermediate. The energy minimization used a new algorithm that increased the speed and eliminated a cut-off for non-bonded interactions. After minimization the models for substrate and tetrahedral intermediate both had root mean square deviations of 0.48 Å for all atoms of the HIV protease compared to the starting crystal structure. Differences in the model structures and interaction energies for HIV protease with different substrates were analyzed. The calculated interaction energies for the 21 HIV protease-tetrahedral intermediate models gave a correlation coefficient of 0.64 with the kinetic measurements. The eight substrates with changes in the P1 and P1' residues next to the scissile bond gave the highest correlation of 0.93, while the 14 substrates with changes in P2-P2' gave a correlation coefficient of 0.86. The catalytic mechanism and factors influencing the catalytic efficiency of the different substrates are discussed in relation to the models. The predictive ability of molecular mechanics calculations is discussed in the context of the statistical mechanics analysis of the differences in free energy.
Keywords: aspartic proteases/calculated interaction energies/HTV protease/substrate binding/transition state
Received October 31, 1994; revised February 26, 1996; accepted March 30, 1996.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Chen, I. T. Weber, R. W. Harrison, and J. Leis Identification of Amino Acids in HIV-1 and Avian Sarcoma Virus Integrase Subsites Required for Specific Recognition of the Long Terminal Repeat Ends J. Biol. Chem., February 17, 2006; 281(7): 4173 - 4182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. T. Weber and R. W. Harrison Molecular mechanics analysis of drug-resistant mutants of HIV protease Protein Eng. Des. Sel., June 1, 1999; 12(6): 469 - 474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Rosin, R. K. Belew, G. M. Morris, A. J. Olson, and D. S. Goodsell Coevolutionary analysis of resistance-evading peptidomimetic inhibitors of HIV-1 protease PNAS, February 16, 1999; 96(4): 1369 - 1374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Tozser, P. Bagossi, I. T. Weber, J. M. Louis, T. D. Copeland, and S. Oroszlan Studies on the Symmetry and Sequence Context Dependence of the HIV-1 Proteinase Specificity J. Biol. Chem., July 4, 1997; 272(27): 16807 - 16814. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. T. Weber, R. W. Harrison, and R. V. Iozzo Model Structure of Decorin and Implications for Collagen Fibrillogenesis J. Biol. Chem., December 13, 1996; 271(50): 31767 - 31770. [Abstract] [Full Text] [PDF]
|
|