8.3 Protein-ligand and protein-protein interactions
3 min read•august 1, 2024
Protein-ligand and protein-protein interactions are crucial for cellular processes. These interactions involve complementary shapes, chemical properties, and water molecules, with hotspot residues playing a key role in binding energy.
Conformational changes can occur upon binding, affecting protein function. Understanding the thermodynamics, kinetics, and biological significance of these interactions is essential for drug discovery and disease treatment.
Protein-Ligand and Protein-Protein Interfaces
Structural Features of Interfaces
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Protein-ligand interfaces characterized by complementary shapes and chemical properties between the protein binding site and the ligand
Protein-protein interfaces involve larger surface areas compared to protein-ligand interfaces with a combination of hydrophobic, electrostatic, and hydrogen-bonding interactions
Protein-ligand interfaces often involve deep binding pockets or clefts on the protein surface (active sites of enzymes), while protein-protein interfaces can be flat or involve interlocking surfaces (antigen-antibody complexes)
Hotspot residues at protein-ligand and protein-protein interfaces contribute disproportionately to the binding energy and are often conserved across related proteins
Role of Water Molecules
Water molecules can play a crucial role in mediating interactions at protein-ligand and protein-protein interfaces by forming bridging hydrogen bonds or being displaced upon binding
Water-mediated interactions can contribute to the specificity and affinity of protein-ligand and protein-protein recognition (water molecules in the of a protein kinase)
Displacement of water molecules from hydrophobic surfaces upon binding can result in a favorable entropic contribution to the free energy of binding (hydrophobic effect)
Conformational Changes in Interactions
Types of Conformational Changes
Conformational changes in proteins can occur upon ligand binding or protein-protein interaction, ranging from small side-chain rearrangements to large-scale domain movements
model suggests that the protein undergoes conformational changes to optimize interactions with the ligand or partner protein (enzyme-substrate binding)
Conformational selection model proposes that the protein pre-exists in multiple conformations and the ligand or partner protein selects the most favorable one (intrinsically disordered proteins)
Functional Consequences of Conformational Changes
Conformational changes can expose or create new binding sites, regulate protein function, or transmit signals across the protein structure
involves conformational changes at a site distant from the , modulating protein activity in response to ligand binding or protein-protein interactions (hemoglobin's cooperative oxygen binding)
Conformational changes can also be involved in the assembly or disassembly of macromolecular complexes (actin filament polymerization)
Thermodynamics and Kinetics of Interactions
Thermodynamic Parameters
Protein-ligand and protein-protein interactions driven by a combination of enthalpic (hydrogen bonding, van der Waals interactions) and entropic (hydrophobic effect, conformational entropy) contributions to the free energy of binding
Dissociation constant (Kd) is a measure of the strength of protein-ligand or protein-protein interactions at equilibrium, with lower Kd values indicating higher affinity
(ITC) can directly measure the thermodynamic parameters (enthalpy, entropy, and free energy) of protein-ligand and protein-protein interactions
Kinetic Parameters
Kinetics of protein-ligand and protein-protein interactions characterized by association (kon) and dissociation (koff) rate constants, which determine the overall affinity and the time course of binding
(SPR) and biolayer interferometry (BLI) are common techniques for measuring the kinetics of protein-ligand and protein-protein interactions in real-time
Kinetic parameters can provide insights into the mechanism of binding, such as the presence of multiple binding steps or conformational changes (two-step binding mechanism)
Biological Significance of Interactions
Cellular Processes
Protein-ligand interactions essential for many biological processes, such as enzyme catalysis (substrate binding), signal transduction (hormone-receptor interactions), and transport of small molecules (oxygen binding to hemoglobin)
Protein-protein interactions form the basis of cellular signaling pathways (kinase cascades), transcriptional regulation (transcription factor-coactivator interactions), and the assembly of macromolecular complexes (ribosome assembly)
Disease and Therapeutic Implications
Dysregulation of protein-ligand or protein-protein interactions can lead to various diseases, such as cancer (oncogenic fusion proteins), autoimmune disorders (self-antigen recognition), and neurodegenerative diseases (protein aggregation)
Protein-ligand interactions are the primary targets for drug discovery, with small molecule inhibitors or activators designed to modulate protein function (kinase inhibitors for cancer therapy)
Protein-protein interactions can be targeted by therapeutic antibodies (monoclonal antibodies against cytokines), peptides (peptide inhibitors of viral entry), or small molecules (small molecule inhibitors of protein-protein interactions) to disrupt pathological interactions or promote beneficial ones
Understanding the structural and biophysical basis of protein-ligand and protein-protein interactions is crucial for designing novel therapeutic interventions and understanding the molecular mechanisms of disease