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 |
|---|---|
| Pages (from-to) | 120-123 |
| Number of pages | 4 |
| Journal | Computer Physics Communications |
| Volume | 179 |
| Issue number | 1-3 |
| DOIs | |
| Publication status | Published - Jul 2008 |
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Keywords
- Car-Parrinello
- DFT
- EVB
- HIV-1 protease
- MP2
ASJC Scopus subject areas
- Computer Science Applications
- Physics and Astronomy(all)
Cite this
On the nature of the reaction intermediate in the HIV-1 protease : a quantum chemical study. / Carnevale, V.; Raugei, Simone; Piana, S.; Carloni, P.
In: Computer Physics Communications, Vol. 179, No. 1-3, 07.2008, p. 120-123.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - On the nature of the reaction intermediate in the HIV-1 protease
T2 - a quantum chemical study
AU - Carnevale, V.
AU - Raugei, Simone
AU - Piana, S.
AU - Carloni, P.
PY - 2008/7
Y1 - 2008/7
N2 - 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.
AB - 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.
KW - Car-Parrinello
KW - DFT
KW - EVB
KW - HIV-1 protease
KW - MP2
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UR - http://www.scopus.com/inward/citedby.url?scp=44649160614&partnerID=8YFLogxK
U2 - 10.1016/j.cpc.2008.01.032
DO - 10.1016/j.cpc.2008.01.032
M3 - Article
VL - 179
SP - 120
EP - 123
JO - Computer Physics Communications
JF - Computer Physics Communications
SN - 0010-4655
IS - 1-3
ER -