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Unraveling the role of protein dynamics in dihydrofolate reductase catalysis

Luk, Louis Yu Pan, Ruiz-Pernia, J. Javier, Dawson, William Michael, Roca, Maite, Loveridge, Edric Joel, Glowacki, David R., Harvey, Jeremy N., Mulholland, Adrian J., Tunon, Inaki, Moliner, Vicent and Allemann, Rudolf Konrad 2013. Unraveling the role of protein dynamics in dihydrofolate reductase catalysis. Proceedings of the National Academy of Sciences of the United States of America 110 (41) , pp. 16344-16349. 10.1073/pnas.1312437110

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Abstract

Protein dynamics have controversially been proposed to be at the heart of enzyme catalysis, but identification and analysis of dynamical effects in enzyme-catalyzed reactions have proved very challenging. Here, we tackle this question by comparing an enzyme with its heavy (15N, 13C, 2H substituted) counterpart, providing a subtle probe of dynamics. The crucial hydride transfer step of the reaction (the chemical step) occurs more slowly in the heavy enzyme. A combination of experimental results, quantum mechanics/molecular mechanics simulations, and theoretical analyses identify the origins of the observed differences in reactivity. The generally slightly slower reaction in the heavy enzyme reflects differences in environmental coupling to the hydride transfer step. Importantly, the barrier and contribution of quantum tunneling are not affected, indicating no significant role for “promoting motions” in driving tunneling or modulating the barrier. The chemical step is slower in the heavy enzyme because protein motions coupled to the reaction coordinate are slower. The fact that the heavy enzyme is only slightly less active than its light counterpart shows that protein dynamics have a small, but measurable, effect on the chemical reaction rate.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Cardiff Catalysis Institute (CCI)
Chemistry
Subjects: Q Science > QD Chemistry
Uncontrolled Keywords: kinetics; computational chemistry; biological chemistry; biophysics; quantum biology
Additional Information: Online publication date: 24 September 2013.
Publisher: National Academy of Sciences
ISSN: 0027-8424
Funders: BBSRC
Last Modified: 05 Jun 2017 04:09
URI: http://orca.cf.ac.uk/id/eprint/51435

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