Substrate Channeling in an Artificial Metabolon: A Molecular Dynamics Blueprint for an Experimental Peptide Bridge

Yuanchao Liu, David P. Hickey, Jing Yao Guo, Erica Earl, Sofiene Abdellaoui, Ross D. Milton, Matthew S. Sigman, Shelley D. Minteer, Scott Calabrese Barton

    Research output: Research - peer-reviewArticle

    • 3 Citations

    Abstract

    Natural enzyme cascades utilize electrostatic guidance as an effective technique to control the diffusion of charged reaction intermediates between catalytic active sites in a process known as substrate channeling. However, the limited understanding of channeling mechanisms has abated the application of this technique in artificial catalytic cascades. In this work, we utilize molecular dynamics simulations to describe the transport of anionic intermediates (e.g., oxalate and glucose-6-phosphate) on a theoretical cationic α-helix peptide bridge and identify rules for molecular-level design of electrostatic channeling. These simulations allowed us to elucidate a surface diffusion mechanism whereby the anionic intermediate undergoes discrete hydrogen-bonding interactions along adjacent cationic residues on the peptide bridge. Using MD simulations as a foundational blueprint, we synthesized an enzyme complex using a poly(lysine) peptide chain as a cationic bridge between glucose-6-phosphate dehydrogenase and hexokinase. Stopped-flow lag time experiments demonstrate the ability of the artificially linked enzyme complex to facilitate electrostatic substrate channeling, while an analogous neutral poly(glycine)-bridged complex was used as a control to isolate proximity effects from artificial substrate channeling.

    LanguageEnglish (US)
    Pages2486-2493
    Number of pages8
    JournalACS Catalysis
    Volume7
    Issue number4
    DOIs
    StatePublished - Apr 7 2017

    Profile

    Blueprints
    Peptides
    Molecular dynamics
    Electrostatics
    Enzymes
    Substrates
    Glucose
    Phosphates
    Reaction intermediates
    Surface diffusion
    Amino acids
    Hydrogen bonds
    Computer simulation
    Experiments
    Oxidoreductases
    Glucose-6-Phosphate
    Hexokinase
    Oxalates
    Glucosephosphate Dehydrogenase
    Glycine

    Keywords

    • electrostatic diffusion
    • enzyme cascade
    • glucose-6-phosphate dehydrogenase
    • hexokinase
    • poly(lysine)
    • surface diffusion

    ASJC Scopus subject areas

    • Catalysis

    Cite this

    Substrate Channeling in an Artificial Metabolon : A Molecular Dynamics Blueprint for an Experimental Peptide Bridge. / Liu, Yuanchao; Hickey, David P.; Guo, Jing Yao; Earl, Erica; Abdellaoui, Sofiene; Milton, Ross D.; Sigman, Matthew S.; Minteer, Shelley D.; Calabrese Barton, Scott.

    In: ACS Catalysis, Vol. 7, No. 4, 07.04.2017, p. 2486-2493.

    Research output: Research - peer-reviewArticle

    Liu, Y, Hickey, DP, Guo, JY, Earl, E, Abdellaoui, S, Milton, RD, Sigman, MS, Minteer, SD & Calabrese Barton, S 2017, 'Substrate Channeling in an Artificial Metabolon: A Molecular Dynamics Blueprint for an Experimental Peptide Bridge' ACS Catalysis, vol 7, no. 4, pp. 2486-2493. DOI: 10.1021/acscatal.6b03440
    Liu Y, Hickey DP, Guo JY, Earl E, Abdellaoui S, Milton RD et al. Substrate Channeling in an Artificial Metabolon: A Molecular Dynamics Blueprint for an Experimental Peptide Bridge. ACS Catalysis. 2017 Apr 7;7(4):2486-2493. Available from, DOI: 10.1021/acscatal.6b03440
    Liu, Yuanchao ; Hickey, David P. ; Guo, Jing Yao ; Earl, Erica ; Abdellaoui, Sofiene ; Milton, Ross D. ; Sigman, Matthew S. ; Minteer, Shelley D. ; Calabrese Barton, Scott. / Substrate Channeling in an Artificial Metabolon : A Molecular Dynamics Blueprint for an Experimental Peptide Bridge. In: ACS Catalysis. 2017 ; Vol. 7, No. 4. pp. 2486-2493
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