Thermodynamics: Protein Folding and Interactions

Gibbs free energy equation: G = H - TS, where G is the Gibbs free energy, H is the enthalpy, T is the temperature in Kelvin, and S is the entropy.

Cyclohexane: Six carbon ring structure which exists in different conformations with different thermodynamic instability

Levinthals paradox: the idea that a protein can fold into its native structure in a remarkably short time despite having an astronomically large number of potential conformations to explore.

KA: Association constant AB/[A][B]. Units M-1

KD: Dissociation constant [A][B] /AB Units M. Concentration of a ligand at which half the receptor sites are occupied.

Cooperativity: When two or more molecules bind to the same receptor molecule , the binding of one molecule affects the binding affinity of additional molecules, leading to increased sensitivity and responsiveness of the receptor to ligand concentrations. e.g. haemoglobin

Myoglobin: monomeric protein that binds to oxygen

Oxygen binding to haem in haemoglobin:

• Oxygen binding is cooperative, meaning that the binding of one oxygen molecule increases the likelihood of additional oxygen molecules binding to the remaining heme groups, enhancing overall oxygen transport efficiency. This is because oxygen binding moves the Fe into the plane of haems tetrapyrol ring making it easier to bind to.

• Cooperativity in oxygen unloading: The cooperative nature of haemoglobin also extends to oxygen unloading, where the release of one oxygen molecule facilitates the release of others from the remaining heme groups, ensuring efficient delivery of oxygen to tissues that require it most.

• The movement of the tetrapyrol ring into the plane moves a proximal histidine and causes conformational change of the polypeptide structure. This changes surface interactions between dimers, influencing the affinity of haemoglobin for oxygen and promoting a more relaxed state that enhances oxygen release under conditions of high demand, such as in exercising muscles.

• T state: This is the tense state of hemoglobin, characterized by a lower affinity for oxygen, which is stabilized when oxygen levels in the environment are low.

• R state: This is the relaxed state of hemoglobin, characterized by a higher affinity for oxygen, which facilitates oxygen binding when levels in the environment are high.

• Allosteric regulation: The binding of molecules such as 2,3-bisphosphoglycerate (2,3-BPG) to hemoglobin promotes the T state, decreasing its affinity for oxygen and thus enhancing oxygen unloading in peripheral tissues. Additionally, factors such as pH and carbon dioxide concentration can also affect hemoglobin's affinity for oxygen, a phenomenon known as the Bohr effect, which further helps to promote oxygen release in metabolically active tissues.