title: Triggering loops and enzyme function: identification of loops that trigger and modulate movements.
abstract: Enzyme function often involves a conformational change. There is a general agreement that loops play a vital role in correctly positioning the catalytically important residues. Nevertheless, predicting the functional loops and most importantly their role in enzyme function remains a difficult task. A major reason for this difficulty is that loops that undergo conformational change are frequently not well conserved in their primary sequence. beta1,4-Galactosyltransferase is one such enzyme. There, the amino acid sequence of a long loop that undergoes a large conformational change upon substrate binding is not well conserved. Our molecular dynamics simulations show that the large conformational change in the long loop is brought about by a second, interacting loop. Interestingly, while the structural change of the second loop is much smaller than that of the long loop, its sequence (particularly glycine residues) is highly conserved. We further examine the generality of the proposition that there are loops that trigger movements but nevertheless show little or no structural changes in crystals. We focus on two other enzymes, enolase and lipase. We chose these enzymes, since they too undergo conformational change upon ligand binding, however, they have different folds and different functions. Through multiple sets of simulations we show that the conformational change of the functional loop(s) is brought about through communication of flexibility by triggering loops that have several glycine residues. We further propose that similar to the conservation of common favorable fold types and structural motifs, evolution has also conserved common "skillful" mechanisms. Mechanisms may be conserved across different folds, sequences and functions, with adaptation to specific enzymatic roles.
authors.affiliation: Basic Research Program, SAIC-Frederick Inc., Laboratory of Experimental and Computational Biology, NCI-Frederick, Bldg. 469 Rm. 151, Frederick, MD 21702, USA.
authors.forename: K
authors.initials: K
authors.lastname: Gunasekaran
authors.forename: Buyong
authors.initials: B
authors.lastname: Ma
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D001051:Apoenzymes / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D020035:Holoenzymes / Q000737:chemistry / Q000378:metabolism; D008049:Lipase / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D009237:N-Acetyllactosamine Synthase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism
chemical_list: D001051:Apoenzymes; D020035:Holoenzymes; D014364:Tryptophan; D009237:N-Acetyllactosamine Synthase; D008049:Lipase; D010751:Phosphopyruvate Hydratase