Computational Prediction of Allosteric Structural Changes by a Simple Mechanical   Model: Application to Hemoglobin T ßà R Transition

Chunyan Xu and Ivet Bahar       Biochemistry, 2002, submitted

 Global dynamics of protein

• Coordinated motions of proteins are known to be relevant to their function.
• The current methods for studying protein dynamics (spectroscopic studies, MD simulation etc.) either suffer from incomplete sampling of comformational space or becomes computationally too expensive.

 Hemoglobin (Hb) 

• Hemoglobin is a model protein to study allosteric protein mechanism.
• Hb has two identical a-chains of 141 amino acids and two b-chains of 146 amino acid each.
• Each subunit has similar 3-d structure and has a heme-binding pocket that bind oxygen.
• The binding of the first O₂ molecule enhances O₂ binding affinity of the other subunits (allosteric effect).
• The allosteric effect is believed to be conveyed by the subunit interfaces.
• Two pdb structures (1a3n and 1bbb) corresponding to the T (unliganded) and R2 (liganded) conformation of Hb were used in this study.

 Model

• We used an analytical approach based on a model originating from statistical mechanics of elastic networks. The earlier version of this model is known as Gaussian network model (GNM).  

• GNM has recently been extended to predict the directionalities of collective motions. This new version, called anisotropic network model (ANM), will be used for comparing dynamics of Hb in T and R2 conformation. We then relate the dynamics of the protein to mechanisms of Hb function.

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