2.4 Thermodynamics of biomolecular interactions

Thermodynamics of biomolecular interactions is all about energy changes when molecules come together. It's like understanding the rules of attraction in the molecular world, using principles from physics to explain why some molecules stick together and others don't.

This topic dives into how energy, heat, and randomness affect biological processes. It's crucial for grasping why proteins fold, how enzymes work, and what makes DNA strands pair up. Basically, it's the science behind life's tiniest building blocks.

Thermodynamics of Biomolecular Interactions

Thermodynamic Principles Governing Biomolecular Interactions

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• The first and second laws of thermodynamics form the foundation for understanding biomolecular interactions and their behavior in biological systems
• Gibbs free energy (ΔG) determines the spontaneity and direction of biomolecular interactions
  • A negative ΔG indicates a spontaneous process (protein folding)
  • A positive ΔG suggests a non-spontaneous process (protein unfolding)
• The change in Gibbs free energy (ΔG) for a biomolecular interaction is determined by the balance between the change in enthalpy (ΔH) and the change in entropy (ΔS), as described by the equation: $ΔG = ΔH - TΔS$, where T is the absolute temperature
• The change in enthalpy (ΔH) represents the heat absorbed or released during the formation of a biomolecular complex (hydrogen bonding), while the change in entropy (ΔS) reflects the change in the degree of disorder or randomness in the system (hydrophobic interactions)

Thermodynamic Equilibrium Constant and Binding Affinity

• The thermodynamic equilibrium constant (K) is related to the Gibbs free energy change (ΔG) through the equation: $ΔG = -RTlnK$, where R is the gas constant and T is the absolute temperature
  • This relationship allows for the determination of binding affinity and the prediction of the direction of biomolecular interactions
  • A higher K value indicates a stronger binding affinity and a more negative ΔG value
• The dissociation constant (Kd) is the reciprocal of the equilibrium constant (K) and represents the concentration of ligand at which half of the available binding sites on the receptor are occupied at equilibrium
  • A lower Kd value indicates a higher binding affinity (antibody-antigen interactions)
  • The relationship between Kd and ΔG is given by the equation: $ΔG = RTlnKd$

Enthalpy and Entropy in Complex Formation

Enthalpy Changes in Biomolecular Interactions

• Enthalpy changes (ΔH) in biomolecular interactions are primarily influenced by the formation and breakage of non-covalent interactions
  • Hydrogen bonds, van der Waals forces, and electrostatic interactions contribute to ΔH
  • Negative ΔH values indicate the formation of favorable interactions and the release of heat (exothermic)
  • Positive ΔH values suggest the breakage of interactions and the absorption of heat (endothermic)
• The strength and number of non-covalent interactions formed during complex formation determine the magnitude of the enthalpy change
  • The formation of a large number of hydrogen bonds between complementary base pairs in DNA duplex formation results in a large negative ΔH value

Entropy Changes in Biomolecular Interactions

• Entropy changes (ΔS) in biomolecular interactions are associated with changes in the degree of disorder or randomness in the system
  • Rearrangement of solvent molecules and conformational changes of the interacting biomolecules contribute to ΔS
  • Positive ΔS values indicate an increase in disorder or randomness, which is entropically favorable (hydrophobic effect)
  • Negative ΔS values suggest a decrease in disorder or randomness, which is entropically unfavorable (restriction of conformational freedom)
• The hydrophobic effect is an entropy-driven process that plays a significant role in the formation of many biomolecular complexes
  • Nonpolar molecules aggregate in aqueous solutions to minimize their contact with water, leading to an increase in entropy (protein folding, lipid membrane assembly)

Interplay between Enthalpy and Entropy in Complex Stability

• The overall spontaneity and stability of biomolecular complexes are determined by the interplay between enthalpy and entropy
  • A favorable (negative) ΔG can result from either a negative ΔH (exothermic process) or a positive TΔS term (entropy-driven process), or a combination of both
  • The relative contributions of enthalpy and entropy to complex stability can vary depending on the specific biomolecular interaction
• Temperature influences the balance between enthalpy and entropy in complex formation
  • At lower temperatures, enthalpy tends to dominate, favoring interactions with negative ΔH values (hydrogen bonding)
  • At higher temperatures, entropy becomes more significant, favoring interactions with positive ΔS values (hydrophobic interactions)

Binding Affinity and Free Energy

Concept of Binding Affinity

• Binding affinity is a measure of the strength of the interaction between two or more biomolecules
  • It quantifies the tendency of the molecules to associate and form a stable complex (ligand-receptor, protein-protein)
  • Higher binding affinity indicates a stronger interaction and a more stable complex
• The dissociation constant (Kd) is commonly used to express binding affinity
  • Kd represents the concentration of ligand at which half of the available binding sites on the receptor are occupied at equilibrium
  • A lower Kd value indicates a higher binding affinity, as it requires a lower concentration of ligand to achieve half-maximal binding (enzyme-substrate, antibody-antigen)

Relationship between Binding Affinity and Free Energy

• The relationship between the dissociation constant (Kd) and the Gibbs free energy change (ΔG) is given by the equation: $ΔG = RTlnKd$, where R is the gas constant and T is the absolute temperature
  • A higher binding affinity (lower Kd) corresponds to a more negative ΔG value, indicating a more thermodynamically favorable interaction
  • The association constant (Ka) is the reciprocal of the dissociation constant (Kd) and is another way to express binding affinity
• The binding affinity of a biomolecular interaction can be influenced by various factors
  • Complementarity of the interacting surfaces, number and strength of non-covalent interactions, and conformational changes associated with complex formation affect binding affinity
  • Mutations in the interacting partners can alter binding affinity by changing the surface complementarity or the non-covalent interactions (point mutations in protein-protein interfaces)

Predicting Stability and Specificity

Predicting Complex Stability

• The stability of a biomolecular complex can be predicted by evaluating the Gibbs free energy change (ΔG) associated with its formation
  • A more negative ΔG value indicates a more stable complex, as it suggests a greater tendency for the complex to form spontaneously
  • The Gibbs-Helmholtz equation, $ΔG = ΔH - TΔS$, can be used to predict the effect of temperature on complex stability
• The effect of temperature on the stability of biomolecular complexes depends on the driving forces of the interaction
  • An increase in temperature will favor the dissociation of the complex if the interaction is enthalpically driven (negative ΔH)
  • An increase in temperature will favor the formation of the complex if the interaction is entropically driven (positive ΔS)

Predicting Interaction Specificity

• The specificity of a biomolecular interaction can be assessed by comparing the binding affinities of a ligand to its target receptor and to other potential off-target receptors
  • A high specificity interaction is characterized by a significantly higher binding affinity for the target receptor compared to the off-target receptors (specific enzyme inhibitors)
  • Mutations in the interacting partners can alter specificity by changing the surface complementarity or the non-covalent interactions
• Mutational analysis can be employed to predict the contribution of specific residues or regions to the stability and specificity of biomolecular interactions
  • Targeted mutations are introduced, and the resulting changes in binding affinity are measured to identify the key determinants of the interaction and assess their thermodynamic roles (alanine scanning mutagenesis)

Influence of Environmental Factors on Stability and Specificity

• The influence of pH and ionic strength on the stability of biomolecular interactions can be predicted by considering their impact on the non-covalent interactions involved in complex formation
  • Changes in pH can alter the protonation state of ionizable groups, affecting electrostatic interactions (histidine protonation)
  • Variations in ionic strength can modulate the screening of charges and the strength of electrostatic interactions (salt bridge formation)
• The presence of cosolvents, such as urea or guanidinium chloride, can affect the stability of biomolecular complexes by altering the solvation properties of the system
  • Cosolvents can disrupt hydrogen bonding networks and weaken hydrophobic interactions, leading to complex dissociation (protein denaturation)