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: Contribution to journalArticle

  • 4 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
Glucose
Phosphates
Substrates
Reaction intermediates
Glucose-6-Phosphate
Hexokinase
Oxalates
Surface diffusion
Glucosephosphate Dehydrogenase
Glycine
Lysine
Amino acids
Hydrogen bonds
Computer simulation
Experiments

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: Contribution to journalArticle

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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