Ab initio QM/MM free-energy studies of arginine deiminase catalysis: The protonation state of the Cys nucleophile

Zhihong Ke, Hua Guo, Daiqian Xie, Shenglong Wang, Yingkai Zhang

Research output: Contribution to journalArticle


The first step of the hydrolytic deimination of l-arginine catalyzed by arginine deiminase is examined using ab initio quantum mechanical/molecular mechanical molecular dynamics simulations. Two possible protonation states of the nucleophilic Cys406 residue were investigated, and the corresponding activation free energies were obtained via umbrella sampling. Our calculations indicated a reaction free-energy barrier of 21.3 kcal/mol for the neutral cysteine, which is in reasonably good agreement with the experimental k cat value of 6.3 s-1, i.e., a barrier of 16.7 kcal/mol. On the other hand, the deprotonated Cys nucleophile yields a free-energy barrier of 6.7 kcal/mol, much lower than the experimental result. The reaction free-energy barriers along with other data suggest that the Cys nucleophile is dominated by its protonated state in the Michaelis complex, and the reaction barrier corresponds largely to its deprotonation.

Original languageEnglish (US)
Pages (from-to)3725-3733
Number of pages9
JournalJournal of Physical Chemistry B
Issue number13
StatePublished - Apr 7 2011


ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

Cite this