Modulating Enzyme Catalysis through Mutations Designed to Alter Rapid Protein Dynamics

Ioanna Zoi, Javier Suarez, Dimitri Antoniou, Scott A. Cameron, Vern L. Schramm, Steven D. Schwartz

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


The relevance of sub-picosecond protein motions to the catalytic event remains a topic of debate. Heavy enzymes (isotopically substituted) provide an experimental tool for bond-vibrational links to enzyme catalysis. A recent transition path sampling study with heavy purine nucleoside phosphorylase (PNP) characterized the experimentally observed mass-dependent slowing of barrier crossing (Antoniou, D.; Ge, X.; Schramm, V. L.; Schwartz, S. D. J. Phys. Chem. Lett. 2012, 3, 3538). Here we computationally identify second-sphere amino acid residues predicted to influence the freedom of the catalytic site vibrational modes linked to heavy enzyme effects in PNP. We mutated heavy and light PNPs to increase the catalytic site vibrational freedom. Enzymatic barrier-crossing rates were converted from mass-dependent to mass-independent as a result of the mutations. The mutagenic uncoupling of femtosecond motions between catalytic site groups and reactants decreased transition state barrier crossing by 2 orders of magnitude, an indication of the femtosecond dynamic contributions to catalysis.

Original languageEnglish (US)
Pages (from-to)3403-3409
Number of pages7
JournalJournal of the American Chemical Society
Issue number10
StatePublished - Mar 16 2016

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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