Targeting a Rate-Promoting Vibration with an Allosteric Mediator in Lactate Dehydrogenase

Michael W. Dzierlenga, Steven D. Schwartz

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


We present a new type of allosteric modulation in which a molecule bound outside the active site modifies the chemistry of an enzymatic reaction through rapid protein dynamics. As a test case for this type of allostery, we chose an enzyme with a well-characterized rate-promoting vibration, lactate dehydrogenase; identified a suitable small molecule for binding; and used transition path sampling to obtain ensembles of reactive trajectories. We found that the small molecule significantly affected the reaction by changing the position of the transition state and, through applying committor distribution analysis, showed that it removed the protein component from the reaction coordinate. The ability of a small-molecule to disrupt enzymatic reactions through alteration of subpicosecond protein motion opens the door for new experimental studies on protein motion coupled to enzymatic reactions and possibly the design of drugs to target these enzymes.

Original languageEnglish (US)
Pages (from-to)2591-2596
Number of pages6
JournalJournal of Physical Chemistry Letters
Issue number13
StatePublished - Jul 7 2016

ASJC Scopus subject areas

  • General Materials Science
  • Physical and Theoretical Chemistry


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