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Mechanistic basis for a connection between the catalytic step and slow opening dynamics of adenylate kinase
Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas, USA.
Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0002-4480-1219
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0002-9098-7974
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2023 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 63, no 5, p. 1556-1569Article in journal (Refereed) Published
Abstract [en]

Escherichia coli adenylate kinase (AdK) is a small, monomeric enzyme that synchronizes the catalytic step with the enzyme’s conformational dynamics to optimize a phosphoryl transfer reaction and the subsequent release of the product. Guided by experimental measurements of low catalytic activity in seven single-point mutation AdK variants (K13Q, R36A, R88A, R123A, R156K, R167A, and D158A), we utilized classical mechanical simulations to probe mutant dynamics linked to product release, and quantum mechanical and molecular mechanical calculations to compute a free energy barrier for the catalytic event. The goal was to establish a mechanistic connection between the two activities. Our calculations of the free energy barriers in AdK variants were in line with those from experiments, and conformational dynamics consistently demonstrated an enhanced tendency toward enzyme opening. This indicates that the catalytic residues in the wild-type AdK serve a dual role in this enzyme’s function─one to lower the energy barrier for the phosphoryl transfer reaction and another to delay enzyme opening, maintaining it in a catalytically active, closed conformation for long enough to enable the subsequent chemical step. Our study also discovers that while each catalytic residue individually contributes to facilitating the catalysis, R36, R123, R156, R167, and D158 are organized in a tightly coordinated interaction network and collectively modulate AdK’s conformational transitions. Unlike the existing notion of product release being rate-limiting, our results suggest a mechanistic interconnection between the chemical step and the enzyme’s conformational dynamics acting as the bottleneck of the catalytic process. Our results also suggest that the enzyme’s active site has evolved to optimize the chemical reaction step while slowing down the overall opening dynamics of the enzyme.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023. Vol. 63, no 5, p. 1556-1569
National Category
Theoretical Chemistry
Research subject
biological chemistry
Identifiers
URN: urn:nbn:se:umu:diva-205159DOI: 10.1021/acs.jcim.2c01629ISI: 000936859400001PubMedID: 36802243Scopus ID: 2-s2.0-85148862970OAI: oai:DiVA.org:umu-205159DiVA, id: diva2:1739271
Funder
Swedish Research Council, 2021-04513NIH (National Institutes of Health), R01GM132481Available from: 2023-02-24 Created: 2023-02-24 Last updated: 2023-03-17Bibliographically approved

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Ojeda-May, PedroÅdén, JörgenWolf-Watz, Magnus

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Ojeda-May, PedroÅdén, JörgenWolf-Watz, MagnusNam, Kwangho
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High Performance Computing Center North (HPC2N)Department of Chemistry
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Journal of Chemical Information and Modeling
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