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 language | English |
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Pages (from-to) | 120-123 |
Number of pages | 4 |
Journal | Computer Physics Communications |
Volume | 179 |
Issue number | 1-3 |
DOIs | |
Publication status | Published - Jul 1 2008 |
Keywords
- Car-Parrinello
- DFT
- EVB
- HIV-1 protease
- MP2
ASJC Scopus subject areas
- Hardware and Architecture
- Physics and Astronomy(all)