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Photo Lynn Kamerlin

Lynn Kamerlin

Professor

Photo Lynn Kamerlin

Role of Ligand-Driven Conformational Changes in Enzyme Catalysis : Modeling the Reactivity of the Catalytic Cage of Triosephosphate Isomerase

Author

  • Yashraj S Kulkarni
  • Qinghua Liao
  • Fabian Byléhn
  • Tina L Amyes
  • John P Richard
  • Shina C L Kamerlin

Summary, in English

We have previously performed empirical valence bond calculations of the kinetic activation barriers, Δ G‡calc, for the deprotonation of complexes between TIM and the whole substrate glyceraldehyde-3-phosphate (GAP, Kulkarni et al. J. Am. Chem. Soc. 2017 , 139 , 10514 - 10525 ). We now extend this work to also study the deprotonation of the substrate pieces glycolaldehyde (GA) and GA·HPi [HPi = phosphite dianion]. Our combined calculations provide activation barriers, Δ G‡calc, for the TIM-catalyzed deprotonation of GAP (12.9 ± 0.8 kcal·mol-1), of the substrate piece GA (15.0 ± 2.4 kcal·mol-1), and of the pieces GA·HPi (15.5 ± 3.5 kcal·mol-1). The effect of bound dianion on Δ G‡calc is small (≤2.6 kcal·mol-1), in comparison to the much larger 12.0 and 5.8 kcal·mol-1 intrinsic phosphodianion and phosphite dianion binding energy utilized to stabilize the transition states for TIM-catalyzed deprotonation of GAP and GA·HPi, respectively. This shows that the dianion binding energy is essentially fully expressed at our protein model for the Michaelis complex, where it is utilized to drive an activating change in enzyme conformation. The results represent an example of the synergistic use of results from experiments and calculations to advance our understanding of enzymatic reaction mechanisms.

Publishing year

2018-03-21

Language

English

Pages

3854-3857

Publication/Series

Journal of the American Chemical Society

Volume

140

Issue

11

Document type

Journal article

Publisher

The American Chemical Society (ACS)

Keywords

  • Biocatalysis
  • Ligands
  • Molecular Structure
  • Protein Conformation
  • Thermodynamics
  • Triose-Phosphate Isomerase/chemistry

Status

Published

ISBN/ISSN/Other

  • ISSN: 1520-5126