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

V. Carnevale, S. Raugei, S. Piana, P. Carloni

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)120-123
Number of pages4
JournalComputer Physics Communications
Volume179
Issue number1-3
DOIs
Publication statusPublished - Jul 1 2008

Keywords

  • Car-Parrinello
  • DFT
  • EVB
  • HIV-1 protease
  • MP2

ASJC Scopus subject areas

  • Hardware and Architecture
  • Physics and Astronomy(all)

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