Question

If hemoglobin has a mutation of the following amino acid residues: His 2, His 143, and Lys 82 which have caused them to be changed to aspartic acid residues, how does this alter hemoglobin’s function? Specifically discuss how this could affect binding with the expected ligand at this site (name this ligand and describe if this interaction be stronger or weaker) and the overall effect to oxygen binding capacity and affinity these mutations have relative to the wild type hemoglobin sequence

Answer 1

1. The role of Histidine 2, Histidine 143 and Lysine 82- These three residues, which all have positive charges are present in the Beta chains of the haemoglobin molecule. These three residues are particularly involved in the Binding of the organic phosphate containing ligands like- 2,3-BPG, ATP.

2. Role of the mutations/Change in Hemoglobin function- If the 3 positively charged amino acids are mutated and changed to Aspartic acid(which is a negatively charged amino acid), the haemoglobin molecule will lose the ability to bind molecule(2,3-BPG) with a Negative charge, since like charges repel each other and thus the Negative charge o the Aspartic acid will repel the negative charge on the phosphate of 2,3-BPG.

                        It is noteworthy to mention here that 2,3-BPG is an important molecule that specifically interacts with the Hemoglobin molecule. Upon interaction, the oxygen-carrying capacity of Hemoglobin decreases and thus the already bound oxygen molecules with the Hb molecule get detached from the molecule. This even especially occurs near the tissues, when Hb-all saturated with Oxygen(carrying from the lungs) goes for delivering it to the tissues. But in order to deliver the oxygen to the tissues, those need to be detached---2,3-BPG does this job.

3. Interaction strength with 2,3-BPG after mutation – after the key residues have been modified, the Hb molecules will no longer be able to bind to 2,3-BPG.

4. Effect of this Mutation on Oxygen affinity and Oxygen binding Capacity- Each Hemoglobin molecule binds 4 oxygen molecule with the Heme group. So this mutation will decrease the binding affinity of Hb towards 2,3-BPG, which will, in turn, increase the Oxygen binding affinity for Hb, but the oxygen-binding capacity remains the same, in comparison to the wild type haemoglobin.