%0 Journal Article
%A Liao, Qinghua
%A Kulkarni, Yashraj
%A Sengupta, Ushnish
%A Petrović, Dušan
%A Mulholland, Adrian J.
%A van der Kamp, Marc W.
%A Strodel, Birgit
%A Kamerlin, Shina Caroline Lynn
%T Loop Motion in Triosephosphate Isomerase Is Not a Simple Open and Shut Case
%J Journal of the American Chemical Society
%V 140
%N 46
%@ 1520-5126
%C Washington, DC
%I American Chemical Society
%M FZJ-2018-07740
%P 15889 - 15903
%D 2018
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:30362343
%U <Go to ISI:>//WOS:000451496800048
%R 10.1021/jacs.8b09378
%U https://juser.fz-juelich.de/record/858904