Reaction mechanism of caspases: Insights from QM/MM Car-Parrinello simulations
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- M Sulpizi
- A Laio
- J VandeVondele
- A Cattaneo
- U Rothlisberger
- P Carloni
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000183923200010&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1002/prot.10275
- eISSN
- 1097-0134
- Externe Identifier
- Clarivate Analytics Document Solution ID: 697BW
- PubMed Identifier: 12833545
- ISSN
- 0887-3585
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
- Schlüsselwörter
- caspases
- cysteine proteases
- reaction mechanism
- first-principles calculations
- QM/MM
- Paginierung
- 212 - 224
- Datum der Veröffentlichung
- 2003
- Status
- Published
- Titel
- Reaction mechanism of caspases: Insights from QM/MM Car-Parrinello simulations
- Sub types
- Article
- Ausgabe der Zeitschrift
- 52
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Abstract
- <jats:title>Abstract</jats:title><jats:p>Caspases are fundamental targets for pharmaceutical interventions in a variety of diseases involving disregulated apoptosis. Here, we present a quantum mechanics/molecular mechanics Car–Parrinello study of key steps of the enzymatic reaction for a representative member of this family, caspase‐3. The hydrolysis of the acyl–enzyme complex is described at the density functional (BLYP) level of theory while the protein frame and solvent are treated using the GROMOS96 force field. These calculations show that the attack of the hydrolytic water molecule implies an activation free energy of ca. Δ<jats:italic>F</jats:italic><jats:sub>A</jats:sub> ≈ 19 ± 4 kcal/mol in good agreement with experimental data and leads to a previously unrecognized gem‐diol intermediate that can readily (Δ<jats:italic>F</jats:italic><jats:sub>A</jats:sub> ≈ 5 ± 3 kcal/mol) evolve to the enzyme products. Our findings assist in elucidating the striking difference in catalytic activity between caspases and other structurally well‐characterized cysteine proteases (papains and cathepsins) and may help design novel transition‐state analog inhibitors. Proteins 2003;52:212–224. © 2003 Wiley‐Liss, Inc.</jats:p>
- Autoren
- M Sulpizi
- A Laio
- J VandeVondele
- A Cattaneo
- U Rothlisberger
- P Carloni
- DOI
- 10.1002/prot.10275
- eISSN
- 1097-0134
- ISSN
- 0887-3585
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- Proteins: Structure, Function, and Bioinformatics
- Sprache
- en
- Online publication date
- 2003
- Paginierung
- 212 - 224
- Datum der Veröffentlichung
- 2003
- Status
- Published
- Herausgeber
- Wiley
- Herausgeber URL
- http://dx.doi.org/10.1002/prot.10275
- Datum der Datenerfassung
- 2023
- Titel
- Reaction mechanism of caspases: Insights from QM/MM Car–Parrinello simulations
- Ausgabe der Zeitschrift
- 52
Data source: Crossref
- Abstract
- Caspases are fundamental targets for pharmaceutical interventions in a variety of diseases involving disregulated apoptosis. Here, we present a quantum mechanics/molecular mechanics Car-Parrinello study of key steps of the enzymatic reaction for a representative member of this family, caspase-3. The hydrolysis of the acyl-enzyme complex is described at the density functional (BLYP) level of theory while the protein frame and solvent are treated using the GROMOS96 force field. These calculations show that the attack of the hydrolytic water molecule implies an activation free energy of ca. DeltaF(A) approximately equal 19 +/- 4 kcal/mol in good agreement with experimental data and leads to a previously unrecognized gem-diol intermediate that can readily (DeltaF(A) approximately equal 5 +/- 3 kcal/mol) evolve to the enzyme products. Our findings assist in elucidating the striking difference in catalytic activity between caspases and other structurally well-characterized cysteine proteases (papains and cathepsins) and may help design novel transition-state analog inhibitors.
- Addresses
- SISSA, International School for Advanced Studies, Trieste, Italy.
- Autoren
- M Sulpizi
- A Laio
- J VandeVondele
- A Cattaneo
- U Rothlisberger
- P Carloni
- DOI
- 10.1002/prot.10275
- eISSN
- 1097-0134
- Externe Identifier
- PubMed Identifier: 12833545
- Open access
- false
- ISSN
- 0887-3585
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- Proteins
- Schlüsselwörter
- Caspases
- Cysteine Proteinase Inhibitors
- Computational Biology
- Molecular Structure
- Hydrolysis
- Catalysis
- Quantum Theory
- Models, Chemical
- Models, Molecular
- Computer Simulation
- Caspase 3
- Sprache
- eng
- Medium
- Paginierung
- 212 - 224
- Datum der Veröffentlichung
- 2003
- Status
- Published
- Datum der Datenerfassung
- 2003
- Titel
- Reaction mechanism of caspases: insights from QM/MM Car-Parrinello simulations.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 52
Data source: Europe PubMed Central
- Abstract
- Caspases are fundamental targets for pharmaceutical interventions in a variety of diseases involving disregulated apoptosis. Here, we present a quantum mechanics/molecular mechanics Car-Parrinello study of key steps of the enzymatic reaction for a representative member of this family, caspase-3. The hydrolysis of the acyl-enzyme complex is described at the density functional (BLYP) level of theory while the protein frame and solvent are treated using the GROMOS96 force field. These calculations show that the attack of the hydrolytic water molecule implies an activation free energy of ca. DeltaF(A) approximately equal 19 +/- 4 kcal/mol in good agreement with experimental data and leads to a previously unrecognized gem-diol intermediate that can readily (DeltaF(A) approximately equal 5 +/- 3 kcal/mol) evolve to the enzyme products. Our findings assist in elucidating the striking difference in catalytic activity between caspases and other structurally well-characterized cysteine proteases (papains and cathepsins) and may help design novel transition-state analog inhibitors.
- Autoren
- M Sulpizi
- A Laio
- J VandeVondele
- A Cattaneo
- U Rothlisberger
- P Carloni
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/12833545
- DOI
- 10.1002/prot.10275
- eISSN
- 1097-0134
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- Proteins
- Schlüsselwörter
- Caspase 3
- Caspases
- Catalysis
- Computational Biology
- Computer Simulation
- Cysteine Proteinase Inhibitors
- Hydrolysis
- Models, Chemical
- Models, Molecular
- Molecular Structure
- Quantum Theory
- Sprache
- eng
- Country
- United States
- Paginierung
- 212 - 224
- Datum der Veröffentlichung
- 2003
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2003
- Titel
- Reaction mechanism of caspases: insights from QM/MM Car-Parrinello simulations.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 52
Data source: PubMed
- Beziehungen:
-