Molecular dynamics simulations of “loop closing” in the enzyme triose phosphate isomerase

• Published in: Journal of molecular biology Vol. 198; no. 3; pp. 533 - 546
• Main Authors: Brown, Frank K., Kollman, Peter A.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 05.12.1987; Elsevier
• Subjects: Acetone - analogs & derivatives; Acetone - metabolism; Analytical, structural and metabolic biochemistry; Animals; Binding Sites; Biological and medical sciences; Carbohydrate Epimerases - metabolism; chickens; Computer Simulation; dihydroxyacetone phosphate; Dihydroxyacetone Phosphate - metabolism; dihydroxyacetone sulfate; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Isomerases; Models, Molecular; muscles; Protein Conformation; Pyrones; Triose-Phosphate Isomerase - metabolism; triosephosphate isomerase; TIM; DHAS; r.m.s; DHAP; Structure activity relation; Conformational dynamics; Active site; Triosephosphate isomerase; Reaction mechanism; Dimer; Conformation
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/0022-2836(87)90298-1

We present molecular dynamics simulations on the active site region of dimeric triose phosphate isomerase (TIM) using the co-ordinates of native chicken muscle TIM as a starting point and performing simulations with no substrate, with dihydroxyacetone phosphate (DHAP), the natural substrate, and with dihydroxyacetone sulfate (DHAS), a substrate analog. Whereas most of the protein moves less than 1 Å during the simulation, some residues in the active site loop move more than 8 Å during the 10.5 picoseconds of dynamics for each of the simulations. Most interestingly, the nature of the loop motion depends on the substrate, with the largest motion found in the presence of DHAP, and only in the presence of DHAP does the loop move to “close off” the active site pocket. The final structure found for the DHAP-chicken TIM complex is qualitatively similar to that described by Alber et al. for DHAP-yeast TIM. Simulations on the monomeric protein gives insight into why the molecule is active only as a dimer.