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 journalArticlepeer-review

16 Citations (Scopus)


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
Issue number1-3
Publication statusPublished - Jul 1 2008


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

ASJC Scopus subject areas

  • Hardware and Architecture
  • Physics and Astronomy(all)

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