Role of Ligand-Driven Conformational Changes in Enzyme Catalysis : Modeling the Reactivity of the Catalytic Cage of Triosephosphate Isomerase
Kulkarni, Yashraj S ; Liao, Qinghua ; Byléhn, Fabian ; Amyes, Tina L ; Richard, John P and Kamerlin, Shina C L LU
(2018)
In Journal of the American Chemical Society
140(11).
p.3854-3857
- Abstract
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... (More)
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.
(Less)
- author
- Kulkarni, Yashraj S
; Liao, Qinghua
; Byléhn, Fabian
; Amyes, Tina L
; Richard, John P
and Kamerlin, Shina C L
LU
- publishing date
- 2018-03-21
- type
- Contribution to journal
- publication status
- published
- keywords
- Biocatalysis, Ligands, Molecular Structure, Protein Conformation, Thermodynamics, Triose-Phosphate Isomerase/chemistry
- in
- Journal of the American Chemical Society
- volume
- 140
- issue
- 11
- pages
- 4 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- scopus:85044363575
- pmid:29516737
- ISSN
- 1520-5126
- DOI
- 10.1021/jacs.8b00251
- language
- English
- LU publication?
- no
- id
- 5c282647-38d5-4f57-86a7-0d7db8142cba
- date added to LUP
- 2025-01-11 21:17:08
- date last changed
- 2025-02-23 07:26:35
@article{5c282647-38d5-4f57-86a7-0d7db8142cba,
abstract = {{<p>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.</p>}},
author = {{Kulkarni, Yashraj S and Liao, Qinghua and Byléhn, Fabian and Amyes, Tina L and Richard, John P and Kamerlin, Shina C L}},
issn = {{1520-5126}},
keywords = {{Biocatalysis; Ligands; Molecular Structure; Protein Conformation; Thermodynamics; Triose-Phosphate Isomerase/chemistry}},
language = {{eng}},
month = {{03}},
number = {{11}},
pages = {{3854--3857}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Journal of the American Chemical Society}},
title = {{Role of Ligand-Driven Conformational Changes in Enzyme Catalysis : Modeling the Reactivity of the Catalytic Cage of Triosephosphate Isomerase}},
url = {{http://dx.doi.org/10.1021/jacs.8b00251}},
doi = {{10.1021/jacs.8b00251}},
volume = {{140}},
year = {{2018}},
}