cwx.prenhall/horton/medialib/media_portfolio/09.html

1. Michael Berger (Center for Brain Research, Medical University Vienna, Austria): Ligand/Receptor Interaction L* http://cwx.prenhall.com/horton/medialib/media_portfolio/09.html

2. Wenn Du mit anderen ein Schiff bauen willst, Antoine de Saint Exupery

3. Wenn Du mit anderen ein Schiff bauen willst, beginne nicht, mit Ihnen Holz zu sammeln, Antoine de Saint Exupery

4. Wenn Du mit anderen ein Schiff bauen willst, beginne nicht, mit Ihnen Holz zu sammeln, sondern wecke in Ihnen die Sehnsucht nach dem großen weiten Meer. Antoine de Saint Exupery

5. What is a receptor?

6. What is a receptor? A physical target mediating the physiological effect of a drug.

7. What is a receptor? A physical target mediating the physiological effect of a drug. What is a ligand?

8. What is a receptor? A physical target mediating the physiological effect of a drug. What is a ligand? A substance that (strongly) binds to a tissue.

9. What is a receptor? A physical target mediating the physiological effect of a drug. What is a ligand? A substance that (strongly) binds to a tissue. What is an agonist?

10. What is a receptor? A physical target mediating the physiological effect of a drug. What is a ligand? A substance that (strongly) binds to a tissue. What is an agonist? A substance that causes an effect, an active change in the target tissue.

11. What is a receptor? A physical target mediating the physiological effect of a drug. What is a ligand? A substance that (strongly) binds to a tissue. What is an agonist? A substance that causes an effect, an active change in the target tissue. What is an antagonist?

12. What is a receptor? A physical target mediating the physiological effect of a drug. What is a ligand? A substance that (strongly) binds to a tissue. What is an agonist? A substance that causes an effect, an active change in the target tissue. What is an antagonist? A substance that blocks the effect of an agonist

13. What is a receptor? A physical target mediating the physiological effect of a drug. What is a ligand? A substance that (strongly) binds to a tissue. What is an agonist? A substance that causes an effect, an active change in the target tissue. What is an antagonist? A substance that blocks the effect of an agonist What is a transmitter?

14. What is a receptor? A physical target mediating the physiological effect of a drug. What is a ligand? A substance that (strongly) binds to a tissue. What is an agonist? A substance that causes an effect, an active change in the target tissue. What is an antagonist? A substance that blocks the effect of an agonist What is a transmitter? A natural agonist released by a cell and acting on a neighboring cell.

15. Association: [BL] B + L BL KA = [B] . [L]

16. Association: [BL] B + L BL KA = [B] . [L] KA: association equilibrium constant

17. Association: [BL] B + L BL KA = [B] . [L] KA: association equilibrium constant Dissociation: [B] . [L] BL B + L KD = [BL] KD: dissociation equilibrium constant

18. Association: [BL] B + L BL KA = [B] . [L] KA: association equilibrium constant dimension: (concentration)-1 Dissociation: [B] . [L] BL B + L KD = [BL] KD: dissociation equilibrium constant

19. Association: [BL] B + L BL KA = [B] . [L] KA: association equilibrium constant dimension: (concentration)-1 Dissociation: [B] . [L] BL B + L KD = [BL] KD: dissociation equilibrium constant dimension: concentration

20. Association: Dissociation: B + L BL BL B + L

21. Association: Dissociation: B + L BL BL B + L Strong binding: equilibrium is on right side on left side

22. Association: Dissociation: B + L BL BL B + L Strong binding: equilibrium is on right side on left side [BL] [B] . [L] KA = << 1 KD = >> 1 [BL] [B] . [L]

23. Association: Dissociation: B + L BL BL B + L Strong binding: equilibrium is on right side on left side [BL] [B] . [L] KA = << 1 KD = >> 1 [BL] [B] . [L] ln KD negativ ln KA positiv

24. Association: Dissociation: B + L BL BL B + L Strong binding: equilibrium is on right side on left side [BL] [B] . [L] KA = << 1 KD = >> 1 [BL] [B] . [L] ln KD negativ ln KA positiv Van't Hoff: ΔGo= - RT . ln KA = + RT . ln KD ΔGo: change in free enthalpy (Gibbs energy) R: universal gas constant, 1.987 cal/(Mol . °K) or 8.314 J/(Mol . °K) T: absolute temperature

25. The Van‘t Hoff equation allows the calculation of the free enthalpy change of a reaction from the reaction‘s equilibrium constant: Van't Hoff: ΔGo= - RT . ln KA = + RT . ln KD ΔGo: change in free enthalpy (Gibbs energy) R: universal gas constant, 1.987 cal/(Mol . °K) or 8.314 J/(Mol . °K) T: absolute temperature

26. Examples for the change in free enthalpy Go in various reactions ΔGo (kcal/Mol) Glucose + 6 O2 6 CO2 + 6 H2O -686 H2 + ½ O2 H2O -46 ATP ADP + Pi -7.3

27. Examples for the change in free enthalpy Go in various reactions ΔGo (kcal/Mol) Glucose + 6 O2 6 CO2 + 6 H2O -686 H2 + ½ O2 H2O -46 ATP ADP + Pi -7.3 In these reactions, Go is reduced (exergonic processes)

28. Examples for the change in free enthalpy Go in various reactions ΔGo (kcal/Mol) Glucose + 6 O2 6 CO2 + 6 H2O -686 H2 + ½ O2 H2O -46 ATP ADP + Pi -7.3 In these reactions, Go is reduced (exergonic processes) Bond dissociation energies HO-H HO· + ·H 118 CH3CH2-H CH3CH2· + ·H 101 CH3-CH3 CH3· + ·CH3 90

29. The free enthalpy change ΔGo of a reaction is composed of 2 terms: Gibbs & Helmholtz: ΔGo = ΔHo – T . ΔSo

30. The free enthalpy change ΔGo of a reaction is composed of 2 terms: Gibbs & Helmholtz: ΔGo = ΔHo – T . ΔSo change in enthalpy

31. The free enthalpy change ΔGo of a reaction is composed of 2 terms: Gibbs & Helmholtz: ΔGo = ΔHo – T . ΔSo change in enthalpy change in entropy, multiplied by absolute temperature

32. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! The free enthalpy change ΔGo of a reaction is composed of 2 terms: Gibbs & Helmholtz: ΔGo = ΔHo – T . ΔSo change in enthalpy change in entropy, multiplied by absolute temperature ln KD = ΔGo / RT = ΔHo / RT - ΔSo / R • KD measured at various temperatures • ln KD plotted against 1/T ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

33. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! ΔHo < 0: exotherm (reaction mixture warms) lg KD 0 - 55 °C 0 °C ΔSo > 0 (order is decreased) -3 - -6 - ● ● ● ● -9 - ‚ ‚ ‚ ‚ 1/T 0.001 0.002 0.003 0.004 Most common case: The warmer (the lower 1/T), the weaker the affinity (the less negative lg KD). ln KD = ΔGo / RT = ΔHo / RT - ΔSo / R • KD measured at various temperatures • ln KD plotted against 1/T lg KD = 0.434 .ΔHo/R . 1/T – 0.434 .ΔSo/R[0.434 = 1/ln10] ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

34. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! ΔHo < 0: exotherm (reaction mixture warms) lg KD 0 - 55 °C 0 °C ΔSo > 0 (order is decreased) -3 - -6 - ● ● ● ● -9 - ‚ ‚ ‚ ‚ 1/T 0.001 0.002 0.003 0.004 Most common case: The warmer (the lower 1/T), the weaker the affinity (the less negative lg KD). Intersection with ordinate gives information about ΔSo. ln KD = ΔGo / RT = ΔHo / RT - ΔSo / R • KD measured at various temperatures • ln KD plotted against 1/T lg KD = 0.434 .ΔHo/R . 1/T – 0.434 .ΔSo/R[0.434 = 1/ln10] ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

35. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! ΔHo < 0: exotherm (reaction mixture warms) lg KD 0 - 55 °C 0 °C ΔSo > 0 (order is decreased) -3 - -6 - ● ● ● ● -9 - ‚ ‚ ‚ ‚ 1/T 0.001 0.002 0.003 0.004 Most common case: The warmer (the lower 1/T), the weaker the affinity (the less negative lg KD). Intersection with ordinate gives information about ΔSo. ln KD = ΔGo / RT = ΔHo / RT - ΔSo / R Slope allows access to ΔHo. • KD measured at various temperatures • ln KD plotted against 1/T lg KD = 0.434 .ΔHo/R. 1/T – 0.434 .ΔSo/R[0.434 = 1/ln10] ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

36. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! ΔHo < 0: exotherm (reaction mixture warms) lg KD 0 - 55 °C 0 °C ΔSo > 0 (order is decreased) ΔSo < 0 (order is increased) -3 - -6 - ● ● ● ● -9 - ‚ ‚ ‚ ‚ 1/T 0.001 0.002 0.003 0.004 lg KD 0 - If order is increased, driving force is even more sensitive to high temperatures -3 - -6 - ● ● ● ● -9 - ‚ ‚ ‚ ‚ 1/T 0.001 0.002 0.003 0.004 ln KD = ΔGo / RT = ΔHo / RT - ΔSo / R • KD measured at various temperatures • ln KD plotted against 1/T lg KD = 0.434 .ΔHo/R . 1/T – 0.434 .ΔSo/R [0.434 = 1/ln10] ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

37. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! ΔHo < 0: exotherm (reaction mixture warms) lg KD 0 - 55 °C 0 °C ΔSo > 0 (order is decreased) ΔSo < 0 (order is increased) -3 - -6 - ● ● ● ● -9 - ‚ ‚ ‚ ‚ 1/T 0.001 0.002 0.003 0.004 lg KD 0 - If order is increased, driving force is even more sensitive to high temperatures -3 - -6 - ● ● ● ● -9 - ‚ ‚ ‚ ‚ 1/T 0.001 0.002 0.003 0.004 It may be difficult to obtain solid data that allow to decide, if ΔSo is > or < 0. ln KD = ΔGo / RT = ΔHo / RT - ΔSo / R • KD measured at various temperatures • ln KD plotted against 1/T lg KD = 0.434 .ΔHo/R . 1/T – 0.434 .ΔSo/R [0.434 = 1/ln10] ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

38. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! ΔHo < 0: exotherm (reaction mixture warms) ΔHo > 0: endotherm (reaction mixture cools) lg KD lg KD 0 - 0 - 55 °C 0 °C ΔSo > 0 (order is decreased) ΔSo < 0 (order is increased) -3 - -3 - -6 - -6 - ● ● ● ● ● ● ● ● -9 - -9 - ‚ ‚ ‚ ‚ ‚ ‚ ‚ ‚ 1/T 1/T 0.001 0.002 0.003 0.004 0.001 0.002 0.003 0.004 lg KD 0 - Endotherm binding is driven by decrease in order only; here, driving force increases with temperature. -3 - -6 - ● ● ● ● -9 - ‚ ‚ ‚ ‚ 1/T 0.001 0.002 0.003 0.004 ln KD = ΔGo / RT = ΔHo / RT - ΔSo / R • KD measured at various temperatures • ln KD plotted against 1/T lg KD = 0.434 .ΔHo/R . 1/T – 0.434 .ΔSo/R [0.434 = 1/ln10] ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

39. Mechanisms contributing to ligand/receptor interaction: • Ionic interaction • Hydrogen bonds • Hydrophobic interaction • Cation/p interaction • Van der Waals interaction

40. ionic interaction e1. e2 attraction between 2 charges depends on D . r2 r ... distance D ... dielectric constant

41. ionic interaction e1. e2 attraction between 2 charges depends on D . r2 r ... distance D ... dielectric constant vacuum ... 1.0 hexane ... 1.9 H2O ... 78

42. ionic interaction e1. e2 attraction between 2 charges depends on D . r2 r ... distance D ... dielectric constant vacuum ... 1.0 hexane ... 1.9 H2O ... 78 In water, ionic interaction is hindered by shells of water molecules surrounding each ion.

43. hydrogen bonds B + L BL Formation of a hydrogen bond is highly exergonic, yields 3-7 kcal/mol

44. hydrogen bonds B + L BL Formation of a hydrogen bond is highly exergonic, yields 3-7 kcal/mol However, enthalpy balance is poor: BH2O + LH2O BL + H2OH2O

45. hydrogen bonds B + L BL Formation of a hydrogen bond is highly exergonic, yields 3-7 kcal/mol However, enthalpy balance is poor: BH2O + LH2O BL + H2OH2O 1. Break this bond.

46. hydrogen bonds B + L BL Formation of a hydrogen bond is highly exergonic, yields 3-7 kcal/mol However, enthalpy balance is poor: BH2O + LH2O BL + H2OH2O 2. Break this bond. 1. Break this bond.

47. hydrogen bonds B + L BL Formation of a hydrogen bond is highly exergonic, yields 3-7 kcal/mol However, enthalpy balance is poor: BH2O + LH2O BL + H2OH2O 2. Break this bond. 1. Break this bond. 3. Form this bond.

48. hydrogen bonds B + L BL Formation of a hydrogen bond is highly exergonic, yields 3-7 kcal/mol However, enthalpy balance is poor: BH2O + LH2O BL + H2OH2O 4. Form this bond. 2. Break this bond. 1. Break this bond. 3. Form this bond.

49. hydrogen bonds B + L BL Formation of a hydrogen bond is highly exergonic, yields 3-7 kcal/mol However, enthalpy balance is poor: BH2O + LH2O BL + H2OH2O 4. Form this bond. 2. Break this bond. 1. Break this bond. 3. Form this bond. Hydrogen bond formation mainly driven by increase in entropy, since the water molecules “get more freedom“ (2 kcal per mol of water).

50. hydrophobic interaction Molecules or parts of molecules („residues“) without charge, that cannot form a hydrogen bond, are called hydrophobic. They aggregate together to reduce the contact with water to a minimum.