Exploring the Common Dynamics of Homologous Proteins. Application to the Globin Family

Maguid, Sandra; Fernández-Alberti, Sebastián; Ferrelli, María Leticia; Echave, Julián

doi:10.1529/biophysj.104.053041

Cited by 66 publications

(75 citation statements)

References 61 publications

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“…Additionally, the different stacking energies might differentiate the migration dynamics of different ligands. The importance of the CD region on the globin heme-binding family has been corroborated by Alberti et al [64]. Using Gaussian network model analysis the authors showed the existence of conserved low frequency collective modes involving the CD helixes and the loop connecting them.…”

Section: Myoglobin Carbon Monoxide Binding and Migrationmentioning

confidence: 76%

QM/MM methods: Looking inside heme proteins biochemisty

Guallar

Wallrapp

2010

Biophysical Chemistry

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Section: Myoglobin Carbon Monoxide Binding and Migrationmentioning

confidence: 76%

QM/MM methods: Looking inside heme proteins biochemisty

Guallar

Wallrapp

2010

Biophysical Chemistry

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“…Normal mode analysis (11,34) indicates largeamplitude motions in the CD loop. Analysis of the crystal structures has revealed greater R/T displacement of the E-helix in the ␤-than in the ␣-chains, like those exhibited by Mb (20), whose CD loop is similar to that of the Hb ␤-chain.…”

Section: Resultsmentioning

confidence: 99%

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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“…In such studies it is usually reported that the lowest, most collective, normal modes are functionally relevant. Only a few studies have addressed the issue of the evolutionary conservation of normal modes (Keskin et al, 2000;Merlino et al, 2003;Maguid et al, 2005). These studies, limited in general to a small set of proteins of the same family or superfamily, have shown that there is a seeming conservation of the lowest collective normal modes.…”

Section: Introductionmentioning

confidence: 99%