🧪 Environmental Effects on pKa

(How a protein’s local environment shifts amino-acid ionization)

🌡️ First: What does pKa actually mean?

• pKa = the pH at which a group is 50% protonated / 50% deprotonated
• If pH < pKa → group tends to keep its proton
• If pH > pKa → group tends to lose its proton

🔑 Key principle: Anything that stabilizes a charge makes that charged form more favorable → shifts pKa accordingly.

🧬 The two residues shown in the figure

The figure compares one acidic residue and one basic residue:

🔴 Glutamate (Glu)

• Native charge: Negative (–)
• Native pKa in water: ~ 4.5
• Loses a proton to become negatively charged

🔵 Lysine (Lys)

• Native charge: Positive (+)
• Native pKa in water: ~ 10.8
• Gains/keeps a proton to remain positively charged

🌊 Baseline: Water (aqueous environment)

💧 Glu in water

• pKa ≈ 4.5
• Water stabilizes the negative charge
• This is the reference (native) state

💧 Lys in water

• pKa ≈ 10.8
• Water stabilizes the positive charge
• Also the native reference state

👉 Water is polar and charge-friendly, so pKa values are “normal”

⚡ Effect of nearby charges

Now the figure shows what happens when other charged residues are nearby.

➖ Negative environment (near negative charges)

Glu (negative residue near negative charges)

• Like charges repel
• Negative form becomes unfavorable
• Glu prefers to stay protonated (neutral)

➡ pKa increases ⬆️ (You need higher pH to force deprotonation)

Lys (positive residue near negative charges)

• Opposite charges attract
• Positive form is stabilized

➡ pKa increases ⬆️ (Lys holds onto its proton more strongly)

➕ Positive environment (near positive charges)

Glu near positive charges

• Opposite charges attract
• Negative form is stabilized

➡ pKa decreases ⬇️ (Glu deprotonates more easily)

Lys near positive charges

• Like charges repel
• Positive form is destabilized

➡ pKa decreases ⬇️ (Lys loses its proton more easily)

🛢️ Hydrophobic environment (non-polar interior)

This is extremely important for protein cores 🧠

Glu in a hydrophobic environment

• Negative charge is very unfavorable
• Water is excluded → no stabilization

➡ pKa increases ⬆️ (Glu stays protonated and neutral)

Lys in a hydrophobic environment

• Positive charge is also unfavorable
• Protonated form destabilized

➡ pKa decreases ⬇️ (Lys tends to lose its proton)

🧠 Big-picture rules (the entire figure distilled)

📌 Rule 1:

Stabilize a charged form → pKa shifts to favor that charge

📌 Rule 2:

Destabilize a charged form → pKa shifts away from that charge

🔄 Summary table

🧬 Why this matters (protein chemistry context)

• Explains why buried residues can have “weird” pKa values
• Critical for:
  • Enzyme active sites ⚙️
  • pH-dependent conformational changes
  • Protein–protein interactions
  • Catalysis and proton transfer

🧠 Key takeaway:

pKa is not a fixed number — it is environment-dependent