1.1 Essential Elements and the HSAB Principle

The specific roles of metal ions in biology can be rationalized using the **Hard-Soft Acid-Base (HSAB) principle**. Hard acids prefer to bind to hard bases, and soft acids to soft bases.

• Hard Acids (e.g., Na+, K+, Mg2+, Ca2+): These ions are small, highly charged, and not easily polarized. They prefer to bind to **hard bases** such as oxygen atoms in water, phosphates (PO4^3-), and carbonates (CO3^2-). This explains why Ca2+ and Mg2+ are crucial for bone structure (with phosphate) and ATP reactions.
• Borderline Acids (e.g., Fe2+, Co2+, Ni2+, Cu2+, Zn2+): These ions have intermediate properties and can bind to both hard and soft bases. They often bind to **nitrogen atoms** in the imidazole ring of histidine residues, which is a key interaction in many metalloenzymes.
• Soft Acids (e.g., Cu+, Ag+, Hg2+): These are larger and more polarizable. They prefer to bind to **soft bases** such as sulfur atoms in cysteine residues.

1.2 Quantitative Analysis of Buffers

The effectiveness of a buffer can be understood using the **Henderson-Hasselbalch equation**:

This equation shows that the buffer is most effective when the pH is close to the pKa of the weak acid. For the bicarbonate buffer system, the pKa is approximately 6.1. The ratio of [HCO3-] to [H2CO3] in blood is about 20:1, which keeps the blood pH at around 7.4.

2.1 Oxygen Transport: Spin State and Cooperativity

The molecular mechanism of hemoglobin’s function is more nuanced than simple binding. It involves the change in the spin state and coordination geometry of the iron atom.

• Deoxyhemoglobin (Tense or T-state): The Fe2+ ion is in a **high-spin** state. Due to its large size, it is pulled approximately 0.4 Å out of the porphyrin ring plane towards the proximal histidine. This puckering of the heme ring is part of the “tense” conformation.
• Oxyhemoglobin (Relaxed or R-state): Upon oxygen binding, the Fe2+ becomes **low-spin**. The ion’s radius shrinks, allowing it to move into the porphyrin ring plane. This movement pulls on the proximal histidine, initiating a cascade of conformational changes throughout the protein’s quaternary structure. These changes, in turn, increase the oxygen affinity of the other three heme units. This is the structural basis for **positive cooperativity**.
• The Bohr Effect Revisited: Protons and CO2 bind to amino acid residues on hemoglobin, forming salt bridges that stabilize the low-affinity T-state, thereby promoting oxygen release in tissues with higher acidity.

2.2 Catalytic Mechanism of Carbonic Anhydrase

The zinc ion’s role in carbonic anhydrase is a prime example of a metal ion activating a substrate. The catalytic cycle is a four-step process:

1. Proton Release: The Zn2+ ion’s strong Lewis acidity lowers the pKa of a coordinated water molecule from 14 to ~7. This facilitates the deprotonation of water, forming a potent nucleophile: Zn-OH-.
2. CO2 Binding and Nucleophilic Attack: A CO2 molecule diffuses into the active site. The Zn-OH- then attacks the carbon atom, forming a coordinated bicarbonate ion.
3. Product Release: A water molecule displaces the bicarbonate from the active site, releasing the product.
4. Regeneration: The active site is regenerated when another water molecule binds to the zinc, restarting the cycle. The enzyme’s catalytic efficiency is further enhanced by a “proton shuttle” mechanism involving a nearby histidine residue.

3.1 Metal-Based Anticancer Drugs: Cisplatin

Cisplatin, or cis-diamminedichloroplatinum(II), is a potent alkylating agent.

• Mechanism: The drug’s activity is highly dependent on its chemical environment. In the high chloride concentration of blood plasma, the drug is stable. However, upon entering the cell, where chloride concentration is low, the chloride ligands undergo a substitution reaction (anation) with water molecules. The resulting positively charged, aquated complex, cis-[Pt(NH3)2(H2O)2]2+, becomes highly reactive.
• DNA Adduct Formation: This reactive complex binds preferentially to the N7 atom of adjacent guanine bases on a single DNA strand, forming a **1,2-intrastrand cross-link**. This specific distortion of the DNA helix is recognized by the cell’s repair machinery but cannot be correctly repaired. This failure leads to the activation of the apoptosis pathway, causing cancer cell death.
• Geometric Isomerism: The trans isomer, transplatin, is inactive because its geometry prevents the formation of the specific 1,2-intrastrand cross-links that trigger apoptosis.

3.2 Chelation Therapy: The Chelate Effect

The efficacy of chelation therapy is explained by the **chelate effect**, a thermodynamic principle.

• Principle: A multidentate ligand (a chelating agent) forms a more stable complex with a metal ion than several monodentate ligands. This is due to a favorable entropy change (ΔS).
• Examples:
  • EDTA is a hexadentate ligand used to chelate heavy metals like Pb2+.
  • D-Penicillamine is a bidentate ligand that chelates copper in Wilson’s disease.