Molecular mechanical properties of short-sequence peptide enzyme mimics

Tsukasa Takahashi, Bao C. Vo Ngo, Leyang Xiao, Gaurav Arya, Michael J. Heller

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


While considerable attempts have been made to recreate the high turnover rates of enzymes using synthetic enzyme mimics, most have failed and only a few have produced minimal reaction rates that can barely be considered catalytic. One particular approach we have focused on is the use of short-sequence peptides that contain key catalytic groups in close proximity. In this study, we designed six different peptides and tested their ability to mimic the catalytic mechanism of the cysteine proteases. Acetylation and deacylation by Ellmans Reagent trapping experiments showed the importance of having phenylalanine groups surrounding the catalytic sites in order to provide greater proximity between the cysteine, histidine, and aspartate amino acid R-groups. We have also carried out all-atom molecular dynamics simulations to determine the distance between these catalytic groups and the overall mechanical flexibility of the peptides. We found strong correlations between the magnitude of fluctuations in the Cys-His distance, which determines the flexibility and interactions between the cysteine thiol and histidine imidazole groups, and the deacylation rate. We found that, in general, shorter Cys-His distance fluctuations led to a higher deacylation rate constant, implying that greater confinement of the two residues will allow a higher frequency of the acetyl exchange between the cysteine thiol and histidine imidazole R-groups. This may be the key to future design of peptide structures with molecular mechanical properties that lead to viable enzyme mimics.

Original languageEnglish (US)
Pages (from-to)463-474
Number of pages12
JournalJournal of Biomolecular Structure and Dynamics
Issue number3
StatePublished - Mar 3 2016
Externally publishedYes


  • enzyme mimics
  • molecular dynamics simulations
  • molecular mechanics
  • peptide

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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