Is dynamics the missing link for understanding enzyme catalysis?
How do enzymes catalyze reactions? There are countless answers of course, but one answer that has gained much attention and popularity in recent years is – through intrinsic dynamics. Is that so? PNAS recently published a paper by Arieh Warshel entitled: “Enzyme millisecond conformational dynamics do not catalyze the chemical step”. Warshel, an avid assailant of the coupling between dynamics and catalysis was met by Martin Karplus, devoted advocate for catalytic dynamics, to engage in a public dispute over the letters section of PNAS. Who do you find more convincing?
Breaking the dynamics myth
The aforementioned paper by Warshel, was followed by a review he authored in “Proteins” which, as the abstract announces:
Dynamics has a role in catalysis
examines the dynamical proposal in a critical way, considering basically all reasonable definitions, including (but not limited to) such proposed effects as “coupling between conformational and chemical motions,” “landscape searches” and “entropy funnels.” It is shown that none of these proposed effects have been experimentally demonstrated to contribute to catalysis, nor are they supported by consistent theoretical studies.
This review cites no less than 11 papers authored by Karplus, the most recent ones are a couple of papers in which thermally driven dynamics on different timescales have been experimentally observed or simulated, and a direct link between micro- to milli-second domain motions and enzymatic function has been established. The model system in this work is the very well-studied adenylate kinase.
In the reference list to this post you can find several reviews on the subject of the coupling between dynamics and catalysis, including the recent, more “critical” review by Warshel. We wanted to get a feeling of the general trend in the community regarding this subject. Please vote in the poll below (without turning it into a popularity contest) as to your stand on the subject. Comments advocating for each of the sides will be much obliged.
Loading ...Warshel’s review and original PNAS paper:
Pisliakov, A., Cao, J., Kamerlin, S., & Warshel, A. (2009). Enzyme millisecond conformational dynamics do not catalyze the chemical step Proceedings of the National Academy of Sciences, 106 (41), 17359-17364 DOI: 10.1073/pnas.0909150106
Kamerlin SC, & Warshel A (2010). At the dawn of the 21st century: Is dynamics the missing link for understanding enzyme catalysis? Proteins, 78 (6), 1339-75 PMID: 20099310
Karplus’s comments:
Karplus, M. (2010). Role of conformation transitions in adenylate kinase Proceedings of the National Academy of Sciences, 107 (17) DOI: 10.1073/pnas.1002180107
Warshel’s reply:
Kamerlin, S., & Warshel, A. (2010). Reply to Karplus: Conformational dynamics have no role in the chemical step Proceedings of the National Academy of Sciences, 107 (17) DOI: 10.1073/pnas.1002658107
Related literature:
Henzler-Wildman KA, Lei M, Thai V, Kerns SJ, Karplus M, & Kern D (2007). A hierarchy of timescales in protein dynamics is linked to enzyme catalysis. Nature, 450 (7171), 913-6 PMID: 18026087
Henzler-Wildman KA, Thai V, Lei M, Ott M, Wolf-Watz M, Fenn T, Pozharski E, Wilson MA, Petsko GA, Karplus M, Hübner CG, & Kern D (2007). Intrinsic motions along an enzymatic reaction trajectory. Nature, 450 (7171), 838-44 PMID: 18026086
Eisenmesser EZ, Bosco DA, Akke M, & Kern D (2002). Enzyme dynamics during catalysis. Science (New York, N.Y.), 295 (5559), 1520-3 PMID: 11859194
Daniel, R., Dunn, R., Finney, J., & Smith, J. (2003). THE ROLE OF DYNAMICS IN ENZYME ACTIVITY Annual Review of Biophysics and Biomolecular Structure, 32 (1), 69-92 DOI: 10.1146/annurev.biophys.32.110601.142445
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