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

V. Carnevale, Simone 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 2008

Fingerprint

Reaction intermediates
protease
human immunodeficiency virus
reaction intermediates
Gems
proteins
Proteins
attack
Electrostatics
electrostatics
valence
Molecules
Carbon
Peptide Hydrolases
carbon
Substrates
water
Water
molecules

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 journalArticle

@article{ff108bf893eb41e2be82e393a7ccd1f7,
title = "On the nature of the reaction intermediate in the HIV-1 protease: a quantum chemical study",
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.",
keywords = "Car-Parrinello, DFT, EVB, HIV-1 protease, MP2",
author = "V. Carnevale and Simone Raugei and S. Piana and P. Carloni",
year = "2008",
month = "7",
doi = "10.1016/j.cpc.2008.01.032",
language = "English",
volume = "179",
pages = "120--123",
journal = "Computer Physics Communications",
issn = "0010-4655",
publisher = "Elsevier",
number = "1-3",

}

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

UR - http://www.scopus.com/inward/record.url?scp=44649160614&partnerID=8YFLogxK

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

AN - SCOPUS:44649160614

VL - 179

SP - 120

EP - 123

JO - Computer Physics Communications

JF - Computer Physics Communications

SN - 0010-4655

IS - 1-3

ER -