Journal Article

FZJ-2018-07740

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Loop Motion in Triosephosphate Isomerase Is Not a Simple Open and Shut Case

Liao, Q. ; Kulkarni, Y. ; Sengupta, U. ; Petrović, D. ; Mulholland, A. J. ; van der Kamp, M. W. ; Strodel, B.FZJ* ; Kamerlin, S. C. L. (Corresponding author)

2018
American Chemical Society Washington, DC

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Please use a persistent id in citations: http://hdl.handle.net/2128/21055  doi:10.1021/jacs.8b09378

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 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.

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Contributing Institute(s):

1. Strukturbiochemie (ICS-6)

Research Program(s):

1. 551 - Functional Macromolecules and Complexes (POF3-551) (POF3-551)

Appears in the scientific report 2018

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