Comparative study of the nucleophilic attack step in the proteases catalytic activity: A theoretical study

Sebastián A. Cuesta, José R. Mora, Cesar H. Zambrano, F. Javier Torres, Luis Rincón

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8 Scopus citations


The nucleophilic attack step of the hydrolysis reaction mechanism of the glycine-glycine peptide bond mediated by the enzymatic action of various proteases was elucidated by means of DFT calculations. Five different protease models were considered; namely: cysteine (Cys), threonine (Thr), serine (Ser), aspartyl (Asp) proteases, and a metalloprotease containing zinc (Zn). The model was simplified in order to gain information about the nucleophilic attack in this type of reaction. As a comparative study, this work is focused on the trend in the reactivity of the models. According to the computed activation energies, the reactivity order was determined as follows Cys < Thr < Ser < Zn < Asp, being in all cases faster than the uncatalysed spontaneous hydrolysis. A further analysis of the reactions by means of the reaction force approach showed that the structural changes accounts for 65–90% of the total activation energy. Moreover, a natural bond orbital analysis allows the reactions to be classified as synchronous with a late transition state for all cases. Systems analogous to the Cys-protease can be proposed as a promising candidate for the design of mimetic systems capable to cleavage amide bonds.

Original languageEnglish (US)
Article numbere1705412
JournalMolecular Physics
Issue number14
StatePublished - Jul 17 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Molecular Biology
  • Condensed Matter Physics
  • Physical and Theoretical Chemistry


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