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Enzymatic transition states and dynamic motion in barrier crossing

Nature Chemical Biology volume 5, pages 551–558 (2009)Cite this article

Abstract

What are the atomic motions at enzymatic catalytic sites on the timescale of chemical change? Combined experimental and computational chemistry approaches take advantage of transition-state analogs to reveal dynamic motions linked to transition-state formation. QM/MM transition path sampling from reactive complexes provides both temporal and dynamic information for barrier crossing. Fast (femtosecond to picosecond) dynamic motions provide essential links to enzymatic barrier crossing by local or promoting-mode dynamic searches through bond-vibrational space. Transition-state lifetimes are within the femtosecond timescales of bond vibrations and show no manifestations of stabilized, equilibrated complexes. The slow binding and protein conformational changes (microsecond to millisecond) also required for catalysis are temporally decoupled from the fast dynamic motions forming the transition state. According to this view of enzymatic catalysis, transition states are formed by fast, coincident dynamic excursions of catalytic site elements, while the binding of transition-state analogs is the conversion of the dynamic excursions to equilibrated states.

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Figure 1: Transition-state stabilization compared to free energy during an enzymatic reaction.
Figure 2: Transition-state structures of PNP and the effect of remote mutations.
Figure 3: BIEs for [5′-3H]inosine, Immucillin-H and DADMe-Immucillin-H to human PNP.
Figure 4: Transition path sampling studies of catalysis by lactate dehydrogenase.
Figure 5: Steps in the phosphorolysis of guanosine by PNP.
Figure 6: The starting point snapshot from a movie demonstrating protein and reactant motion for barrier crossing in human PNP by transition-path sampling.

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  1. Steven D. Schwartz is in the Department of Biochemistry and the Department of Physiology and Biophysics, and Vern L. Schramm is in the Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.,

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Correspondence to Vern L Schramm.

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V.L.S. is a consultant to, and shareholder in, BioCryst Pharmaceuticals Inc., which is conducting clinical trials with ImmH (tradename Forodesine) and DADMe-ImmH (tradename BCX-4298) under license from the Albert Einstein College of Medicine, Bronx, New York, USA, and Industrial Research Inc., Lower Hutt, New Zealand.

Supplementary information

Supplementary Movie 1

A snapshot from a movie of the 250 fsec period demonstrating protein and reactant motion for barrier crossing in human PNP by TPS. The movie begins with guanosine and phosphate as reactants and the transition state barrier is crossed during this 250 fsec movie followed by automatic movie recycling. The time for the commitment probability to go from zero to unity (Figure 5E) is shown in the movie by migration of C1' of the ribosyl group from guanine (blue) to the phosphate oxygen (red and green). The transition state lifetime is the time when reactants show equal probability of converting to product or reactant (0.5 probability in Figure 5E). The transition state lifetime in the movie is 10 fsec. For comparison, each stretching mode of the 5'-OH bond (in H-bond contact to HSE257:CA) is approximately 9 fsec. At the transition state, C1' is equidistant from N9 of guanine and the phosphate oxygen. Protein conformational changes involved in reactant (S) binding, loop motion and catalytic site organization typically requires µsec to msec and a similar time is needed to clear the catalytic site of products. As 1 msec = 1012 fsec, conformational changes leading to barrier crossing are very slow relative to transition state lifetime. The promoting vibrations include local catalytic site motions occurring on the fsec time scale, and are active throughout the 1 to 10 msec organizational period. The probability of reaching the transition state barrier is based on dynamic probability of correct slow and fast conformational states. With permission of the publisher33. (MPG 1723 kb)

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Schwartz, S., Schramm, V. Enzymatic transition states and dynamic motion in barrier crossing. Nat Chem Biol 5, 551–558 (2009). https://doi.org/10.1038/nchembio.202

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