title: Unsuspected pathway of the allosteric transition in hemoglobin.
abstract: Large conformational transitions play an essential role in the function of many proteins, but experiments do not provide the atomic details of the path followed in going from one end structure to the other. For the hemoglobin tetramer, the transition path between the unliganded (T) and tetraoxygenated (R) structures is not known, which limits our understanding of the cooperative mechanism in this classic allosteric system, where both tertiary and quaternary changes are involved. The conjugate peak refinement algorithm is used to compute an unbiased minimum energy path at atomic detail between the two end states. Although the results confirm some of the proposals of Perutz [Perutz MF (1970) Stereochemistry of cooperative effects in haemoglobin. Nature 228:726-734], the subunit motions do not follow the textbook description of a simple rotation of one αβ-dimer relative to the other. Instead, the path consists of two sequential quaternary rotations, each involving different subdomains and axes. The quaternary transitions are preceded and followed by phases of tertiary structural changes. The results explain the recent photodissociation measurements, which suggest that the quaternary transition has a fast (2 μs) as well as a slow (20 μs) component and provide a testable model for single molecule FRET experiments.
authors.affiliation: Interdisziplinäres Zentrum für Wissenschaftliches Rechnen-Computational Biochemistry, Im Neuenheimer Feld 368, University of Heidelberg, D-69120 Heidelberg, Germany. stefan.fischer@iwr.uni-heidelberg.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Fischer
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Olsen
authors.forename: Kwangho
authors.initials: K
authors.lastname: Nam
authors.forename: Martin
authors.initials: M
authors.lastname: Karplus
mesh_terms: D000494:Allosteric Regulation; D006454:Hemoglobins / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry
chemical_list: D006454:Hemoglobins; D021122:Protein Subunits