Targeting a Rate-Promoting Vibration with an Allosteric Mediator in Lactate Dehydrogenase.
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.
Department of Chemistry and Biochemistry, University of Arizona , 1306 East University Blvd., Tucson, Arizona 85721, United States.
Michael W
MW
Dzierlenga
Department of Chemistry and Biochemistry, University of Arizona , 1306 East University Blvd., Tucson, Arizona 85721, United States.
Steven D
SD
Schwartz
D000494:Allosteric Regulation; D000495:Allosteric Site; D020134:Catalytic Domain; D007770:L-Lactate Dehydrogenase / Q000737:chemistry*; D008958:Models, Molecular; D011487:Protein Conformation; D014732:Vibration
D007770:L-Lactate Dehydrogenase