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Loop Motion in Triosephosphate Isomerase Is Not a Simple Open and Shut Case

Loop Motion in Triosephosphate Isomerase Is Not a Simple Open and Shut Case

Qinghua Liao, Yashraj Kulkarni, Ushnish Sengupta, Dušan Petrović, Adrian J Mulholland, Marc W van der Kamp, Birgit Strodel, Shina Caroline Lynn Kamerlin

J Am Chem Soc. 2018 Nov 21;140(46):15889-15903.

PMID: 30362343

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP9023783-A	Triosephosphate Isomerase from baker's yeast (S. cerevisiae)		9023-78-3	Price

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