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
