- Conformational changes in the receptor cause pH changes in the blood stream which shows the need for a blood buffer system. 
- In physiological conditions, hemoglobin releases protons once oxygen binds, and it decreases the pH in the blood. It causes hemoglobin to bind less oxygen. This is known as the Bohr effect after Christian Bohr. 
- Physiologically, it is key in transporting oxygen from the lungs to the tissues and then moving CO2 from the respiration to the lungs (See figure). 
- CO2 made in the tissues moves  to the capillaries and dissolves to form bicarbonate (HCO3-) slowly (See figure). 	
- RBC contains carbonic anhydrase that accelerates the reaction so most of the CO2 in the blood is carried as bicarbonate (to prevent CO2 bubbles in the blood) (See figure). 


The Bohr Effect

- R-state is the conformational state of oxyhemoglobin.
- When oxygen binds, it “flattens” the iron complex. 
- To prevent steric clash during flattening of the heme, there is an alpha helix that tilts as well.
- Overall, changes in hemoglobin's conformational states at the tertiary level cannot occur without causing quaternary structure changes in the whole protein. 

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- Tetramer of myoglobin-like polypeptides (dimer of alpha beta subunits)
- Delivers oxygen to tissues throughout the body.
- Once oxygen binds, structural change causes oxygen binding affinity to grow in the three other binding sites
- Hemoglobin has two conformation states:
  - T-state
  - R-state


Hemoglobin

Voet, D., Voet, J. G., & Pratt, C. W. (2013). Chapter 7: Protein Function: Myoglobin and Hemoglobin, Muscle Contractions, and Antibodies. In Fundamentals of biochemistry: Life at the molecular level (4th ed., pp. 176-216). Hoboken, NJ: Wiley. Retrieved February 21, 2021, from archive.org.

Fundamental of biochemistry: Life of the molecular level 4th edition: Chapter 7

- A flat ring that contains an iron atom in the center that binds the oxygen atom in a reversible reaction to be able to release oxygen.
- The heme group binds to myoglobin 
- Heme binds four times to hemoglobin 
- Oxygenation of heme causes hemoglobin to change color from dark purple to a scarlet color. 
- In addition to oxygen, however, it can bind things like NO, CO, and H2S and they bind to a higher affinity than oxygen which is evidence of the toxicity of CO.
- CO has a 200-fold greater affinity for hemoglobin than oxygen. 

Heme

- The hemoglobin curve has a sigmoidal (S-shaped) curve instead of the hyperbolic curve for myoglobin.
- Cooperative interaction between the binding sites is displayed, because once a single oxygen binds to hemoglobin the affinity for oxygen at the other sites increases affinity for oxygen at the other subunits. 
- As more oxygen atoms bind to hemoglobin, the slope of the curve increases. 
- Hemoglobin is more saturated with oxygen in arterial oxygen pressures and in venous oxygen pressures hemoglobin is only about half saturated with oxygen. 
- Additionally, the background indicates the color change that occurs with oxygen binding to hemoglobin (blue to red). 


Hemoglobin binding curve

There are many diseases associated with mutations in hemoglobin.
- Sickle-cell anemia 
- Polycythemia 
- Cyanosis
- Hemolytic anemia

Mutations in hemoglobin

- There are additional compounds in the blood stream that effect the oxygen levels besides CO2
- The compound 2,3-bisphosphoglycerate (BPG) binds to deoxyhemoglobin (empty O2 bound hemoglobin) 
- BPG in blood decreases the oxygen affinity by keeping hemoglobin in the deoxyhemoglobin conformation. 
- In the absence of BPG, O2 would not release from the hemoglobin.

2,3-bisphosphoglycerate (BPG)

-  The T-state is the hemoglobin conformational state of deoxyhemoglobin, or the hemoglobin without oxygen bound.
- The iron is situated 6 Angstroms out of the heme and allows for the iron to access oxygen. 


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