Diffusion control in biochemical specificity

Jose L. Alejo, Christopher P. Kempes, Katarzyna P. Adamala

Research output: Contribution to journalArticlepeer-review


Biochemical specificity is critical in enzyme function, evolution, and engineering. Here we employ an established kinetic model to dissect the effects of reactant geometry and diffusion on product formation speed and accuracy in the presence of cognate (correct) and near-cognate (incorrect) substrates. Using this steady-state model for spherical geometries, we find that, for distinct kinetic regimes, the speed and accuracy of the reactions are optimized on different regions of the geometric landscape. From this model we deduce that accuracy can be strongly dependent on reactant geometric properties even for chemically limited reactions. Notably, substrates with a specific geometry and reactivity can be discriminated by the enzyme with higher efficacy than others through purely diffusive effects. For similar cognate and near-cognate substrate geometries (as is the case for polymerases or the ribosome), we observe that speed and accuracy are maximized in opposing regions of the geometric landscape. We also show that, in relevant environments, diffusive effects on accuracy can be substantial even far from extreme kinetic conditions. Finally, we find how reactant chemical discrimination and diffusion can be related to simultaneously optimize steady-state flux and accuracy. These results highlight how diffusion and geometry can be employed to enhance reaction speed and discrimination, and similarly how they impose fundamental restraints on these quantities.

Original languageEnglish (US)
Pages (from-to)1541-1548
Number of pages8
JournalBiophysical journal
Issue number8
StatePublished - Apr 19 2022

Bibliographical note

Funding Information:
This work was supported by NSF grant 1840301, John Templeton Foundation grant 61184, the NASA grant 80NSSC17K0295, and by HHMI Hanna Gray award to J.L.A. The authors thank Artemy Kolchinsky for helpful discussions and comments on the manuscript.

Publisher Copyright:
© 2022 Biophysical Society

PubMed: MeSH publication types

  • Journal Article
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't


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