Hemoglobin consilient mechanism

Immediately below, we note the historical case of oxygen transport by hemoglobin from lungs to the tissues and note how this would be discussed in terms of the consilient mechanism. This was the first biological system appreciated for its positive cooperativity, the cooperative binding of oxygen molecules that is key to successful transport. 

To the best of my knowledge, the hemoglobin oxygenation curve is historically the first example of a biologically essential positive cooperativity. Because of this, it becomes an important objective to explore the phenomenology of hemoglobin s positive cooperativity and compare it with that of the consilient mechanism due to an apolar-polar repulsive free energy of hydration (as is done in Chapter 7) and, in fact, to do so for a number of protein-based machines that exhibit positive cooperativity. 

Is the Consilient Mechanism Relevant to Oxygen Binding by Hemoglobin ... 

Should the structural data show the a p -a p interface to be one of hydrophobic association that is disrupted on oxygenation, then in our view the answer is clearly yes, the cooperative binding of oxygen to hemoglobin results from the consilient mechanism. In our view the presence of hydrophobic association at the a P -a P interface would indicate that positive cooperativity, essential to hemoglobin function in oxygen transport, arises due to the consilient... 

Yet much more phenomenological data, showing the coherence of phenomena between hemoglobin function and the consilient mechanism of the inverse temperature transition for hydrophobic association, continues below, before direct examination of the molecular structures, as generally presented. Subsequently, in section 7.3, the molecular structures are examined to look for the specific interactions most significant to the consilient mechanism. 

Figure 7.9. Mean residue hydropho-bicity plots of the a-chain (A) and the P-chain (B) of hemoglobin and of myoglobin (C). The strong hydrophobidty peaks just above 100 residues are responsible for stable formation of the a P dimer. The strong hydrophobidty peaks near 40 residues may be considered part of the switch region. TTiese hydrophobic residues provide an arc for hydrophobic association at the a P -a P interface. By the consilient mechanism, decreased heme hydropho-bicity on oxygen binding relaxes this inter-dimer hydrophobic assodation and allows the T R transition, as shown in Figure 7.10, to occur. This is further visualized in Figure 7.18 as discussed in the text. See text for further discussion.

Despite the above noted correlation of phenomena, current descriptions of molecular structure and resulting function of hemoglobin and myoglobin (as well as of muscle contraction to be addressed at the molecular level in Chapter 8) proceed without consideration of the consilient mechanism. th the consilient mechanism in mind, however, a distinctive way of looking at protein structure and function materializes. The availability of so many protein crystal structures from The Protein Data Bank and, as employed in our case, the capacity to... 

The phenomenological observations detailed above in section 7.2.4 clearly exhibit a coherence of phenomena with the consilient mechanism. Our objective, therefore, is to determine the particular expressions of the consilient mechanism at the molecular level. As a starting point, we look from the aqueous medium to the heme group in its protein setting and make gross comparison between the heme environment in myoglobin and the environments of the hemes of hemoglobin. In our view, the first clue... 

Tlie Consilient Mechanism Summarized as the Source of the Sigmoid Oxygen Binding of Hemoglobin... 

Accordingly, the important oxygen transport capacity of hemoglobin and the disease state of sickle cell anemia are explicable in terms of spatially localized and moveable cusps of insolubility, that is, water solubility-insolubility divides, in terms of the consilient mechanism. 

As with hemoglobin, discussed in Chapter 7, a Bohr effect occurs with cytochrome c oxidase. Again from the viewpoint of the hydrophobic consilient mechanism, these phenomena are analogous. Formation of the less polar states on reduction of Complex IV and on forming deoxyhemoglobin result in proton uptake, whereas formation of the more polar oxidized state of Complex IV and the more polar oxygenated state of hemoglobin result in proton release. This is as expected from the AG, of the comprehensive hydrophobic effect, as discussed above. 

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