Interdisziplinäres Zentrum für Wissenschaftliches Rechnen-Computational Biochemistry, Im Neuenheimer Feld 368, University of Heidelberg, D-69120 Heidelberg, Germany.
Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5608-13. doi: 10.1073/pnas.1011995108. Epub 2011 Mar 17.
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.
大的构象转变在许多蛋白质的功能中起着至关重要的作用，但实验并不能提供从一种结构到另一种结构的路径的原子细节。对于血红蛋白四聚体，未配位（T）和四氧合（R）结构之间的转变路径尚不清楚，这限制了我们对这个经典变构系统中协同机制的理解，其中涉及三级和四级变化。共轭峰精修算法用于在两个末端状态之间以原子细节计算无偏最小能量路径。尽管结果证实了珀西特[Perutz MF（1970）血红蛋白协同效应的立体化学。自然 228：726-734]的一些建议，但亚基运动并不遵循教科书上关于一个αβ-二聚体相对于另一个简单旋转的描述。相反，该路径由两个连续的四级旋转组成，每个旋转涉及不同的亚结构域和轴。四级转变之前和之后是三级结构变化的阶段。结果解释了最近的光解测量，这表明四级转变既有快速（2 μs）又有缓慢（20 μs）成分，并为单分子 FRET 实验提供了一个可测试的模型。
