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On the nature of the reaction intermediate in the HIV-1 protease: a quantum chemical study (Articolo in rivista)

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On the nature of the reaction intermediate in the HIV-1 protease: a quantum chemical study (Articolo in rivista) (literal)

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Carnevale, V; Raugei, S; Piana, S; Carloni, P (2008)
On the nature of the reaction intermediate in the HIV-1 protease: a quantum chemical study
in Computer physics communications
(literal)

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\"Scuola Int Super Studi Avanzati, I-34014 Trieste, Italy; CNR INFM Democritos, I-34014 Trieste, Italy; [Piana, S.] Curtin Univ Technol, Nanochem Res Inst, Perth, WA 6845, Australia (literal)

Titolo

On the nature of the reaction intermediate in the HIV-1 protease: a quantum chemical study (literal)

Abstract

Several mechanistic aspects of Aspartic Proteases' enzymatic reaction are currently highly controversial. There is general consensus that the first step of the reaction involves a nucleophilic attack of a water molecule to the substrate carbonyl carbon with subsequent formation of a metastable intermediate (INT). However, the exact nature of this intermediate is subject of debate. While ab initio and QM/MM calculations predict that INT is a neutral gem-diol specie, empirical valence bond calculations suggest that the protein frame can stabilize a charged oxyanion intermediate. Here the relative stability of the gem diol and oxyanion intermediate is calculated by performing density functional and post-Hartree-Fock calculations. The robustness of the results is assessed by increasing the size of the system and of the basis set and by performing QM/MM calculations that explicitly include protein/solvent electrostatic effects. Our results suggest that the neutral gem-diol intermediate is 20-30 kcal/mol more stable than the charged oxyanion. It is therefore concluded that only the neutral specie is populated during the enzymatic reaction. (C) 2008 Elsevier B.V. All rights reserved. (literal)

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