New Insights into the Allosteric Mechanism of Human Hemoglobin from Molecular Dynamics Simulations

Mouawad, Liliane; Pérahia, David; Robert, Charles H.; Guilbert, Christophe

doi:10.1016/s0006-3495(02)75665-8

Cited by 51 publications

(59 citation statements)

References 62 publications

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“…However, because of hemoglobin's large size, early computer simulation studies on HbA have either been restricted to only a part of the protein (17)(18)(19)(20), or relatively short time simulations for the entire protein (21)(22)(23)(24). More recently, longer simulations of hemoglobin on nanosecond time scale became possible (25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Role of the Subunit Interactions in the Conformational Transitions in Adult Human Hemoglobin: An Explicit Solvent Molecular Dynamics Study

et al. 2012

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Hemoglobin exhibits allosteric structural changes upon ligand binding due to the dynamic interactions between the ligand binding sites, the amino acids residues and some other solutes present under physiological conditions. In the present study, the dynamical and quaternary structural changes occurring in two unligated (deoxy-) T structures, and two fully ligated (oxy-) R, R2 structures of adult human hemoglobin were investigated with molecular dynamics. It is shown that, in the sub-microsecond time scale, there is no marked difference in the global dynamics of the amino acids residues in both the oxy-and the deoxy-forms of the individual structures. In addition, the R, R2 are relatively stable and do not present quaternary conformational changes within the time scale of our simulations while the T structure is dynamically more flexible and exhibited the T→R quaternary conformational transition, which is propagated by the relative rotation of the residues at the α 1 β 2 and α 2 β 1 interface.

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Section: Introductionmentioning

confidence: 99%

Role of the Subunit Interactions in the Conformational Transitions in Adult Human Hemoglobin: An Explicit Solvent Molecular Dynamics Study

et al. 2012

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“…Consequently, a number of calculations to simulate the quaternary transition of Hb have been made. They include a rigid body model (17), an implementation of targeted molecular dynamics (18), and a normal mode analysis (19). In this paper, we have used the conjugate peak refinement (CPR) method (20) to determine the minimum energy pathway (MEP) involved in the transition.…”

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Unsuspected pathway of the allosteric transition in hemoglobin

Fischer

Olsen

Nam

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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.conformational change | cooperativity | domain motion | protein hinges M any proteins undergo large conformational transitions that are essential for their functions (1-3). The transitions can occur in monomers such as the myosin molecular motor (4-6), in multisubunit complexes such as the chaperone GroEL (7), and in systems such as the flagellar motor of bacteria, which is composed of several hundred proteins (8). Probably the most studied example is the T (tense) to R (relaxed) transition in the vertebrate hemoglobin tetramer (Hb) (9-11), for which the conformational transition increases the efficiency of oxygen transport. Hemoglobin, which is composed of two identical α-and two identical β-subunits, is the paradigm for the development of models of cooperativity and allosteric regulation in proteins (9-13). Phenomenologically, the positive cooperativity involves the increase in the affinity for oxygen of unliganded subunits upon the successive binding of oxygen to other subunits. This is achieved by structural changes within subunits (tertiary changes) and between subunits (quaternary changes). Based on the superposition of the crystallographic structures for the deoxy unliganded T state and the fully liganded R state of the protein, the quaternary T → R transition has been described as involving primarily an approximately 15°rotation of one "dimer" (α 1 β 1 ) relative to the other (α 2 β 2 ) around a virtual axis (Fig. 1A) (9, 14). Together with a small relative translation of the αβ-dimers, this reduces the central cavity between the dimers (a channel along the C2 axis of symmetry), where the heterotropic effector 2,3-bisphosphoglycerate is bound in the T state. An important aspect of these structural ch...

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“…Interest in Hb continues to the present, with new experimental and theoretical methods aimed at characterizing intermediate ligation states of the molecule (3)(4)(5) and at gaining a deeper understanding of its allosteric transition (6)(7)(8)(9)(10)(11).…”

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A quantum-chemical picture of hemoglobin affinity

Alcantara

Spiro

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Understanding the molecular mechanism of hemoglobin cooperativity remains an enduring challenge. Protein forces that control ligand affinity are not directly accessible by experiment. We demonstrate that computational quantum mechanics/molecular mechanics methods can provide reasonable values of ligand binding energies in Hb, and of their dependence on allostery. About 40% of the binding energy differences between the relaxed state and tense state quaternary structures result from strain induced in the heme and its ligands, especially in one of the pyrrole rings. The proximal histidine also contributes significantly, in particular, in the ␣-chains. The remaining energy difference resides in protein contacts, involving residues responsible for locking the quaternary changes. In the ␣-chains, the most important contacts involve the FG corner, at the ''hinge'' region of the ␣1␤2 quaternary interface. The energy differences are spread more evenly among the ␤-chain residues, suggesting greater flexibility for the ␤-than for the ␣-chains along the quaternary transition. Despite this chain differentiation, the chains contribute equally to the relaxed substitute state energy difference. Thus, nature has evolved a symmetric response to the quaternary structure change, which is a requirement for maximum cooperativity, via different mechanisms for the two kinds of chains.allostery ͉ cooperativity ͉ heme ͉ quantum mechanics/molecular mechanics H emoglobin has been a paradigm for our understanding of multisubunit proteins, beginning with the pioneering work of Adair (1) and then with the elucidation of the oxygenated and deoxygenated crystal structures of Hb by Perutz (2), some four decades ago. Interest in Hb continues to the present, with new experimental and theoretical methods aimed at characterizing intermediate ligation states of the molecule (3-5) and at gaining a deeper understanding of its allosteric transition (6-11).The Hb molecule is composed of four chains that contain a heme group capable of reversibly binding CO or O 2 . The molecule is arranged as a dimer of dimers, where each dimer is made up of an ␣-and a ␤-chain (denoted as ␣ 1 ␤ 1 or ␣ 2 ␤ 2 ) with a hydrophobic intradimer interface. Adair observed that Hb binds oxygen in a cooperative manner, successive ligation events occurring with higher affinity. For some time it was believed that such cooperativity could be explained by direct interaction of the closely packed heme groups. However the 1960s saw the appearance of the first allosteric models for Hb cooperativity. In particular, the Monod-Wyman-Changeux (12) model postulated the existence of two states of the molecule: the relaxed (R) state with high ligand affinity and the tense (T) state with low affinity. Ligand binding preferentially stabilized the R form and led to cooperativity. Early Hb crystallization attempts revealed that deoxy crystals would shatter when exposed to oxygen, which suggested that a quaternary rearrangement was associated with the T-R transition of the molecule.Crystal structure...

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New Insights into the Allosteric Mechanism of Human Hemoglobin from Molecular Dynamics Simulations

Cited by 51 publications

References 62 publications

Role of the Subunit Interactions in the Conformational Transitions in Adult Human Hemoglobin: An Explicit Solvent Molecular Dynamics Study

Role of the Subunit Interactions in the Conformational Transitions in Adult Human Hemoglobin: An Explicit Solvent Molecular Dynamics Study

Unsuspected pathway of the allosteric transition in hemoglobin

A quantum-chemical picture of hemoglobin affinity

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