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A density functional study of the hydrogen‐bond network within the HIV‐1 protease catalytic site cleft
Author(s) -
Sirois S.,
Proynov E. I.,
Truchon J.F.,
Tsoukas C. M.,
Salahub D. R.
Publication year - 2003
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.10176
Subject(s) - protonation , chemistry , active site , catalytic triad , catalysis , protease , hydrogen bond , hiv 1 protease , monomer , acetic acid , amine gas treating , interaction energy , stereochemistry , crystallography , computational chemistry , enzyme , molecule , organic chemistry , ion , polymer
The relative energy between two different protonation sites of the Asp25′ catalytic site residue is computed and analyzed for various HIV‐1 Protease/inhibitor complexes and compared to the wild‐type structure. By comparing calculations of negatively charged fragments of gradually increasing size up to 105 atoms we show that correct modeling of the HIV‐1 Protease active site requires much larger models than the commonly used acetic acid/acetate moieties. The energy difference between the two proposed protonation sites decreases as the size of the system increases and tends to converge only when the entire catalytic triad of both monomers is taken into account. The importance of the Gly27 backbone amine groups in the stabilization of the negative charge within the catalytic site cleft is revealed. Comparison of the wild‐type structure with the structures from various Pr/drug complexes indicates that the HIV‐1 protease has a particular catalytic site flexibility. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1110–1119, 2003