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000858904 1001_ $$0P:(DE-HGF)0$$aLiao, Qinghua$$b0
000858904 245__ $$aLoop Motion in Triosephosphate Isomerase Is Not a Simple Open and Shut Case
000858904 260__ $$aWashington, DC$$bAmerican Chemical Society$$c2018
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000858904 520__ $$aConformational 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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000858904 7001_ $$0P:(DE-HGF)0$$aKulkarni, Yashraj$$b1
000858904 7001_ $$0P:(DE-HGF)0$$aSengupta, Ushnish$$b2
000858904 7001_ $$0P:(DE-Juel1)165744$$aPetrović, Dušan$$b3
000858904 7001_ $$00000-0003-1015-4567$$aMulholland, Adrian J.$$b4
000858904 7001_ $$00000-0002-8060-3359$$avan der Kamp, Marc W.$$b5
000858904 7001_ $$0P:(DE-Juel1)132024$$aStrodel, Birgit$$b6
000858904 7001_ $$00000-0002-3190-1173$$aKamerlin, Shina Caroline Lynn$$b7$$eCorresponding author
000858904 773__ $$0PERI:(DE-600)1472210-0$$a10.1021/jacs.8b09378$$gVol. 140, no. 46, p. 15889 - 15903$$n46$$p15889 - 15903$$tJournal of the American Chemical Society$$v140$$x1520-5126$$y2018
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