Large-scale allosteric conformational transitions of adenylate kinase appear to involve a population-shift mechanism. Export

@article{citeulike:1912202, abstract = {Large-scale conformational changes in proteins are often associated with the binding of a substrate. Because conformational changes may be related to the function of an enzyme, understanding the kinetics and energetics of these motions is very important. We have delineated the atomically detailed conformational transition pathway of the phosphotransferase enzyme adenylate kinase (AdK) in the absence and presence of an inhibitor. The computed free energy profiles associated with conformational transitions offer detailed mechanistic insights into, as well as kinetic information on, the ligand binding mechanism. Specifically, potential of mean force calculations reveal that in the ligand-free state, there is no significant barrier separating the open and closed conformations of AdK. The enzyme samples near closed conformations, even in the absence of its substrate. The ligand binding event occurs late, toward the closed state, and transforms the free energy landscape. In the ligand-bound state, the closed conformation is energetically most favored with a large barrier to opening. These results emphasize the underlying dynamic nature of the enzyme and indicate that the conformational transitions in AdK are more intricate than a mere two-state jump between the crystal-bound and -unbound states. Based on the existence of the multiple conformations of the enzyme in the open and closed states, a different viewpoint of ligand binding is presented. Our estimated activation energy barrier for the conformational transition is also in reasonable accord with the experimental findings.}, author = {Arora, Karunesh and Brooks, Charles L.}, citeulike-article-id = {1912202}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0706443104}, citeulike-linkout-1 = {http://www.pnas.org/content/104/47/18496.full.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/104/47/18496.full.full.pdf}, citeulike-linkout-3 = {http://www.pnas.org/cgi/content/abstract/104/47/18496}, citeulike-linkout-4 = {http://view.ncbi.nlm.nih.gov/pubmed/18000050}, citeulike-linkout-5 = {http://www.hubmed.org/display.cgi?uids=18000050}, day = {20}, doi = {10.1073/pnas.0706443104}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {activation, conformational\_changes, energy\_landscape, kinetics, switch}, month = {November}, number = {47}, pages = {18496--18501}, posted-at = {2009-10-28 13:38:02}, priority = {2}, title = {Large-scale allosteric conformational transitions of adenylate kinase appear to involve a population-shift mechanism.}, url = {http://dx.doi.org/10.1073/pnas.0706443104}, volume = {104}, year = {2007} }

TY - JOUR ID - citeulike:1912202 L3 - citeulike-article-id:1912202 N2 - Large-scale conformational changes in proteins are often associated with the binding of a substrate. Because conformational changes may be related to the function of an enzyme, understanding the kinetics and energetics of these motions is very important. We have delineated the atomically detailed conformational transition pathway of the phosphotransferase enzyme adenylate kinase (AdK) in the absence and presence of an inhibitor. The computed free energy profiles associated with conformational transitions offer detailed mechanistic insights into, as well as kinetic information on, the ligand binding mechanism. Specifically, potential of mean force calculations reveal that in the ligand-free state, there is no significant barrier separating the open and closed conformations of AdK. The enzyme samples near closed conformations, even in the absence of its substrate. The ligand binding event occurs late, toward the closed state, and transforms the free energy landscape. In the ligand-bound state, the closed conformation is energetically most favored with a large barrier to opening. These results emphasize the underlying dynamic nature of the enzyme and indicate that the conformational transitions in AdK are more intricate than a mere two-state jump between the crystal-bound and -unbound states. Based on the existence of the multiple conformations of the enzyme in the open and closed states, a different viewpoint of ligand binding is presented. Our estimated activation energy barrier for the conformational transition is also in reasonable accord with the experimental findings. IS - 47 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 1091-6490 EP - 18501 TI - Large-scale allosteric conformational transitions of adenylate kinase appear to involve a population-shift mechanism. VL - 104 SP - 18496 KW - activation KW - conformational_changes KW - energy_landscape KW - kinetics KW - switch AU - Arora, Karunesh AU - Brooks, Charles PY - 2007/11/20/ UR - http://dx.doi.org/10.1073/pnas.0706443104 ER -