Loop Motion in Triosephosphate Isomerase Is Not a Simple Open and Shut Case
Liao, Qinghua ; Kulkarni, Yashraj ; Sengupta, Ushnish ; Petrović, Dušan ; Mulholland, Adrian J ; van der Kamp, Marc W ; Strodel, Birgit and Kamerlin, Shina Caroline Lynn LU
(2018)
In Journal of the American Chemical Society
140(46).
p.15889-15903
- Abstract
Conformational changes are crucial for the catalytic action of many enzymes. A prototypical and well-studied example is loop opening and closure in triosephosphate isomerase (TIM), which is thought to determine the rate of catalytic turnover in many circumstances. Specifically, TIM loop 6 "grips" the phosphodianion of the substrate and, together with a change in loop 7, sets up the TIM active site for efficient catalysis. Crystal structures of TIM typically show an open or a closed conformation of loop 6, with the tip of the loop moving ∼7 Å between conformations. Many studies have interpreted this motion as a two-state, rigid-body transition. Here, we use extensive molecular dynamics simulations, with both conventional and enhanced... (More)
Conformational changes are crucial for the catalytic action of many enzymes. A prototypical and well-studied example is loop opening and closure in triosephosphate isomerase (TIM), which is thought to determine the rate of catalytic turnover in many circumstances. Specifically, TIM loop 6 "grips" the phosphodianion of the substrate and, together with a change in loop 7, sets up the TIM active site for efficient catalysis. Crystal structures of TIM typically show an open or a closed conformation of loop 6, with the tip of the loop moving ∼7 Å between conformations. Many studies have interpreted this motion as a two-state, rigid-body transition. Here, we use extensive molecular dynamics simulations, with both conventional and enhanced sampling techniques, to analyze loop motion in apo and substrate-bound TIM in detail, using five crystal structures of the dimeric TIM from Saccharomyces cerevisiae. We find that loop 6 is highly flexible and samples multiple conformational states. Empirical valence bond simulations of the first reaction step show that slight displacements away from the fully closed-loop conformation can be sufficient to abolish most of the catalytic activity; full closure is required for efficient reaction. The conformational change of the loops in TIM is thus not a simple "open and shut" case and is crucial for its catalytic action. Our detailed analysis of loop motion in a highly efficient enzyme highlights the complexity of loop conformational changes and their role in biological catalysis.
(Less)
- author
- Liao, Qinghua
; Kulkarni, Yashraj
; Sengupta, Ushnish
; Petrović, Dušan
; Mulholland, Adrian J
; van der Kamp, Marc W
; Strodel, Birgit
and Kamerlin, Shina Caroline Lynn
LU
- publishing date
- 2018-11-21
- type
- Contribution to journal
- publication status
- published
- keywords
- Molecular Dynamics Simulation, Molecular Structure, Saccharomyces cerevisiae/enzymology, Triose-Phosphate Isomerase/chemistry
- in
- Journal of the American Chemical Society
- volume
- 140
- issue
- 46
- pages
- 15 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- scopus:85056482355
- pmid:30362343
- ISSN
- 1520-5126
- DOI
- 10.1021/jacs.8b09378
- language
- English
- LU publication?
- no
- id
- a5b1b534-d780-4938-8850-42e3a61a9610
- date added to LUP
- 2025-01-11 20:29:35
- date last changed
- 2025-04-20 11:47:35
@article{a5b1b534-d780-4938-8850-42e3a61a9610,
abstract = {{<p>Conformational changes are crucial for the catalytic action of many enzymes. A prototypical and well-studied example is loop opening and closure in triosephosphate isomerase (TIM), which is thought to determine the rate of catalytic turnover in many circumstances. Specifically, TIM loop 6 "grips" the phosphodianion of the substrate and, together with a change in loop 7, sets up the TIM active site for efficient catalysis. Crystal structures of TIM typically show an open or a closed conformation of loop 6, with the tip of the loop moving ∼7 Å between conformations. Many studies have interpreted this motion as a two-state, rigid-body transition. Here, we use extensive molecular dynamics simulations, with both conventional and enhanced sampling techniques, to analyze loop motion in apo and substrate-bound TIM in detail, using five crystal structures of the dimeric TIM from Saccharomyces cerevisiae. We find that loop 6 is highly flexible and samples multiple conformational states. Empirical valence bond simulations of the first reaction step show that slight displacements away from the fully closed-loop conformation can be sufficient to abolish most of the catalytic activity; full closure is required for efficient reaction. The conformational change of the loops in TIM is thus not a simple "open and shut" case and is crucial for its catalytic action. Our detailed analysis of loop motion in a highly efficient enzyme highlights the complexity of loop conformational changes and their role in biological catalysis.</p>}},
author = {{Liao, Qinghua and Kulkarni, Yashraj and Sengupta, Ushnish and Petrović, Dušan and Mulholland, Adrian J and van der Kamp, Marc W and Strodel, Birgit and Kamerlin, Shina Caroline Lynn}},
issn = {{1520-5126}},
keywords = {{Molecular Dynamics Simulation; Molecular Structure; Saccharomyces cerevisiae/enzymology; Triose-Phosphate Isomerase/chemistry}},
language = {{eng}},
month = {{11}},
number = {{46}},
pages = {{15889--15903}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Journal of the American Chemical Society}},
title = {{Loop Motion in Triosephosphate Isomerase Is Not a Simple Open and Shut Case}},
url = {{http://dx.doi.org/10.1021/jacs.8b09378}},
doi = {{10.1021/jacs.8b09378}},
volume = {{140}},
year = {{2018}},
}