Generation of a dataset for studying ligand effect on homodimer interface

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• Protein dimers are crucial for biological functions, with their stability and specificity governed by interface properties.
• While homodimer interactions are well-studied, the influence of non-peptide ligands on these interfaces remains largely unexplored.
• Understanding ligand effects on protein-protein interactions is vital for drug development.

Purpose of the Study:

• To investigate the impact of interface ligands on the structural and chemical properties of protein homodimer interfaces.
• To quantify changes in hydrophobicity and interface area upon ligand binding.
• To determine the threshold of ligand coverage affecting dimer interactions.

Main Methods:

• Generation of a dataset comprising 62 identical homodimer pairs, with and without interface ligands.
• Comparative analysis of geometric and chemical properties (hydrophobicity, interface area) between ligand-bound and ligand-free homodimer interfaces.
• Statistical evaluation of the correlation between ligand coverage and changes in interface characteristics.

Main Results:

• Homodimer interfaces with bound ligands exhibit reduced hydrophobicity and smaller interface areas compared to ligand-free counterparts.
• Ligands occupying 7% or less of the homodimer interface area demonstrate a negligible effect on dimer interaction.
• The presence of ligands significantly alters the physicochemical nature of the dimer interface.

Conclusions:

• Interface ligands can modulate protein homodimer stability and specificity by altering interface properties.
• The extent of ligand coverage is a critical factor in determining the influence of ligands on dimer interactions.
• Findings provide insights into ligand-mediated regulation of protein-protein interactions, relevant for therapeutic strategies.